CN117729923A - Combination therapy for the treatment of abnormal cell growth - Google Patents

Abstract

The present invention relates to methods, compositions and oral dosage forms for the treatment of abnormal cell growth (e.g., cancer) using SHP2 inhibitors, SOS1 inhibitors, ERK1/2 inhibitors, CDK4/6 inhibitors, AKT inhibitors, mTOR inhibitors, pan-HER inhibitors or EGFR inhibitors in combination with MEK inhibitors or dual RAF/MEK inhibitors.

Description

Combination therapy for the treatment of abnormal cell growth

Cross Reference to Related Applications

The present application claims U.S. provisional patent application Ser. No. 63/146,349 to 5.2021, U.S. provisional patent application Ser. No. 63/185,651 to 5.2021, U.S. provisional patent application Ser. No. 63/146,352 to 5.2021, U.S. provisional patent application Ser. No. 63/185,672 to 5.2021, U.S. provisional patent application Ser. No. 63/146,395 to 5.2021, U.S. provisional patent application Ser. No. 63/185,695 to 5.2021, U.S. provisional patent application Ser. No. 63/146,357 to 5.2021, U.S. provisional patent application Ser. No. 63/185,704 to 7.5.2021, U.S. provisional patent application Ser. No. 63/146,369 to 5.2.2021, and priority and benefit of U.S. provisional patent application Ser. No. 63/146,376 to 5.2.2021.

Background

Components of the RAS/RAF/MEK/ERK (MAPK) pathway represent an opportunity to treat abnormal cell growth (e.g., cancer). Selective inhibitors of certain components of the RAS/RAF/MEK/ERK pathway (e.g., RAS, RAF, MEK and ERK) are useful for treating abnormal cell growth, particularly cancer, in mammals. Targeting multiple nodes in the MAPK pathway simultaneously (vertical inhibition) may improve response (e.g., anti-tumor response, such as depth and/or duration) compared to blocking a single node in the pathway. Furthermore, the efficacy of MAPK pathway blockade may be circumvented by activation of drug resistant pathways, and thus co-targeting MAPK pathways and related parallel pathways may be desirable.

Due to the severity and breadth of diseases and conditions associated with abnormal cell growth (e.g., cancer), effective treatments and methods of treatment are needed. The compounds, compositions, combinations, and methods described herein are directed to this end.

Summary of The Invention

Simultaneous targeting of multiple nodes in the MAPK pathway (e.g., using SHP2 inhibitors, SOS1 inhibitors, ERK1/2 inhibitors, pan-HER inhibitors, or EGFR inhibitors), or co-targeting of the MAPK pathway and related parallel pathways (e.g., using CDK4/6 inhibitors, AKT inhibitors, or mTOR inhibitors) may improve responses (e.g., anti-tumor responses such as depth and/or duration). Thus, provided herein, in part, are combinations (e.g., combinations of compounds described herein, e.g., SHP2 inhibitors, SOS1 inhibitors, ERK1/2 inhibitors, CDK4/6 inhibitors, AKT inhibitors, mTOR inhibitors, pan-HER inhibitors, or EGFR inhibitors in combination with MEK inhibitors or dual RAF/MEK inhibitors) that are useful, e.g., in methods of treating abnormal cell growth (e.g., cancer) in a subject in need thereof.

Accordingly, in one aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a combination of an SHP2 inhibitor and a MEK inhibitor, thereby treating the subject.

In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a combination of an SHP2 inhibitor and a dual RAF/MEK inhibitor, thereby treating the subject.

In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a combination of a SOS1 inhibitor and a MEK inhibitor, thereby treating the subject.

In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a SOS1 inhibitor in combination with a dual RAF/MEK inhibitor, thereby treating the subject.

In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a combination of an ERK1/2 inhibitor and a MEK inhibitor, thereby treating the subject.

In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a combination of an ERK1/2 inhibitor and a dual RAF/MEK inhibitor, thereby treating the subject.

In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a CDK4/6 inhibitor in combination with a MEK inhibitor, thereby treating the subject.

In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a CDK4/6 inhibitor in combination with a dual RAF/MEK inhibitor, thereby treating the subject.

In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a combination of an AKT inhibitor and a MEK inhibitor, thereby treating the subject.

In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a combination of an AKT inhibitor and a dual RAF/MEK inhibitor, thereby treating the subject.

In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a combination of an mTOR inhibitor and a MEK inhibitor, thereby treating the subject.

In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a mTOR inhibitor in combination with a dual RAF/MEK inhibitor, thereby treating the subject.

In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a combination of a pan-HER inhibitor and a MEK inhibitor, thereby treating the subject.

In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a pan-HER inhibitor in combination with a dual RAF/MEK inhibitor, thereby treating the subject.

In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a combination of an EGFR inhibitor and a MEK inhibitor, thereby treating the subject.

In one aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a combination of an EGFR inhibitor and a dual RAF/MEK inhibitor, thereby treating the subject.

In some embodiments, the dual RAF/MEK inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the dual RAF/MEK inhibitor is a potassium salt of a compound of formula (I). Other pharmaceutically acceptable salts of the compounds of formula (I) are contemplated in the methods of treatment disclosed herein.

Other objects and advantages will become apparent to those skilled in the art from consideration of the detailed description, examples and claims that follow.

Drawings

FIG. 1A shows an exemplary CellTiter-Glo assay for assessing cell viability of 16 KRAS G12C, G D or G12V mutant cell lines (9 NSCLCs and 7 PDACs) grown under 3D conditions in a 7 day assay for VS-6766, RMS-4550 and TNO 155.

FIG. 1B shows the IC50 for VS-6766, TNO155 and RMC-4550.

FIG. 2A shows an exemplary CTG proliferation assay using VS-6766 and TNO155 in H2122 cells.

FIG. 2B shows an exemplary synergy analysis using VS-6766 and TNO155 in H2122 cells.

Fig. 2C shows an exemplary waterfall plot summarizing the combined synergy of VS-6766+tno155 in a set of KRAS mut NSCLC and PDAC cell lines.

Fig. 3A shows an exemplary waterfall plot summarizing the combined synergy of VS-6766+ tno155 in a set of KRAS mut NSCLC and PDAC cell lines.

FIG. 3B shows exemplary data for a combination of VS-6766 and TNO155 showing an increase in anti-tumor response in H2122 cells.

FIG. 4A shows an exemplary waterfall graph summarizing the combined synergy of VS-6766+RMC-4550 in a set of KRAS mut NSCLC and PDAC cell lines.

FIG. 4B shows exemplary data for a combination of VS-6766 and RMC-4550, which shows an increase in anti-tumor response in H2122 cells.

FIG. 5A shows exemplary changes in tumor volume in H2122 tumor-bearing mice treated with VS-6766 (0.3 mg/kg QD) +/-RMC-4550 (10 mg/kg QD).

FIG. 5B shows exemplary changes in tumor volume in H2122 tumor-bearing mice treated with VS-6766 (0.3 mg/kg QD) +/-TNO155 (15 mg/kg BID).

Fig. 6A shows an exemplary CellTiter-Glo assay for assessing cell viability of 16 KRAS G12C, G D or G12V mutant cell lines (9 NSCLC and 7 PDACs) grown under 3D conditions in a 7 day assay.

FIG. 6B shows IC 50's for VS-6766 and BI 3406.

FIG. 7A shows an exemplary CTG proliferation assay using VS-6766 and BI3406 in H2122 cells.

FIG. 7B shows an exemplary synergy analysis using VS-6766 and BI3406 in H2122 cells.

FIG. 7C shows an exemplary waterfall plot summarizing the combined synergistic results of VS-6766+BI3406 in a set of KRAS mut NSCLC and PDAC cell lines.

FIG. 8A shows an exemplary waterfall plot summarizing the combined synergistic results of VS-6766+BI3406 in a set of KRAS mut NSCLC and PDAC cell lines.

FIG. 8B shows exemplary data for a combination of VS-6766 and BI3406 showing an increase in anti-tumor response in H2122 cells.

FIG. 9 shows exemplary changes in tumor volume in H2122 tumor-bearing mice treated with VS-6766 (0.3 mg/kg QD) +/-BI-3406 (50 mg/kg BID).

FIG. 10A shows an exemplary CellTiter-Glo assay for assessing cell viability of 16 KRAS G12C, G D or G12V mutant cell lines (9 NSCLCs and 7 PDACs) grown under 3D conditions in a 7 day assay for VS-6766 and LY-3214996.

FIG. 10B shows the IC50 for VS-6766 and LY-3214996.

FIG. 11A shows an exemplary CTG proliferation assay using VS-6766 and LY-3214996 in H2122 cells.

FIG. 11B shows an exemplary synergy analysis using VS-6766 and LY-3214996 in H2122 cells.

FIG. 11C shows an exemplary waterfall plot summarizing the combined synergistic results of VS-6766+LY-3214996 in a set of KRAS mut NSCLC and PDAC cell lines.

FIG. 12A shows an exemplary waterfall graph summarizing the combined synergistic results of VS-6766+LY-3214996 in a set of KRAS mut NSCLC and PDAC cell lines.

FIG. 12B shows exemplary data for a combination of VS-6766 and LY-3214996, which shows an increase in anti-tumor response in H2122 cells.

FIG. 13 shows exemplary changes in tumor volume in H2122 tumor-bearing mice treated with VS-6766 (0.3 mg/kg QD) +/-LY-3214996 (60 mg/kg QD).

Fig. 14A shows an exemplary CellTiter-Glo assay for assessing cell viability of 16 KRAS G12C, G D or G12V mutant cell lines (9 NSCLC and 7 PDACs) grown under 3D conditions in a 7 day assay for VS-6766, palbociclib and arbeli.

Fig. 14B shows IC50 s for VSVS-6766, palbociclib, and abbe's.

FIG. 15A shows an exemplary CTG proliferation assay using VS-6766 and palbociclib in A427 cells.

FIG. 15B shows an exemplary synergy analysis using VS-6766 and palbociclib in A427 cells.

Fig. 15C shows an exemplary waterfall plot summarizing the combined synergy of VS-6766+ palbociclib in a set of KRAS mut NSCLC and PDAC cell lines.

Fig. 16A shows an exemplary waterfall plot summarizing the combined synergy of VS-6766+ palbociclib in a set of KRAS mut NSCLC and PDAC cell lines.

FIG. 16B shows exemplary data for a combination of VS-6766 and palbociclib showing an increase in anti-tumor response in A427 cells.

Fig. 17A shows an exemplary waterfall plot summarizing the combined synergy of VS-6766+ abbe silli in a set of KRAS mut NSCLC and PDAC cell lines.

FIG. 17B shows exemplary data for a combination of VS-6766 and Abeli, showing an increase in anti-tumor response in A427 cells.

FIG. 18 shows exemplary changes in tumor volume in H2122 tumor-bearing mice treated with VS-6766 (0.3 mg/kg QD) +/-Abeli (25 mg/kg QD).

FIG. 19A shows an exemplary Bliss, loewe, HSA and ZIP synergy analysis for VS-6766+ arbelide in ER+ breast cancer cells.

Fig. 19B shows an exemplary Bliss synergy score for VS-6766+ abbe-cili in mcf7er+ breast cancer cells.

FIG. 19C shows an exemplary Bliss synergy score for VS-6766+ Abeli in ZR-75-1ER+ breast cancer cells.

Fig. 20A shows an exemplary CellTiter-Glo assay for assessing cell viability of 16 KRAS G12C, G D or G12V mutant cell lines (9 NSCLC and 7 PDACs) grown under 3D conditions in a 7 day assay for VS-6766, patatib (iptaseptib), M2698 and everolimus.

Fig. 20B shows IC50 s for VSVS-6766, patatine, M2698 and everolimus.

FIG. 21A shows an exemplary CTG proliferation assay using VS-6766 and M2698 in SW1573 cells.

FIG. 21B shows an exemplary synergy analysis using VS-6766 and M2698 in SW1573 cells.

Fig. 21C shows an exemplary waterfall plot summarizing the combined synergy of VS-6766+m2698 in a set of KRAS mut NSCLC and PDAC cell lines.

Fig. 22A shows an exemplary graph summarizing the combined synergistic results of VS-6766+ patadine in a set of KRAS mut NSCLC and PDAC cell lines.

Fig. 22B shows exemplary data for the combination of VS-6766 and patadine, which shows an increase in anti-tumor response in SW1573 cells.

Fig. 23A shows an exemplary graph summarizing the combined synergy of VS-6766+m2698 in a set of KRAS mut NSCLC and PDAC cell lines.

FIG. 23B shows exemplary data for a combination of VS-6766 and M2698, which shows an increase in anti-tumor response in SW1573 cells.

Fig. 24A shows an exemplary graph summarizing the combined synergy of VS-6766+ everolimus in a set of KRAS mut NSCLC and PDAC cell lines.

Fig. 24B shows exemplary data for a combination of VS-6766 and everolimus, showing an increase in anti-tumor response in SW1573 cells.

Fig. 25A shows an exemplary CellTiter-Glo assay for assessing cell viability of 16 KRAS G12C, G D or G12V mutant cell lines (9 NSCLC and 7 PDACs) grown under 3D conditions in a 7 day assay for VS-6766 and afatinib.

FIG. 25B shows the IC50 for VS-6766 and afatinib.

FIG. 26A shows an exemplary CTG proliferation assay using VS-6766 and afatinib in H2122.

FIG. 26B shows an exemplary synergy analysis using VS-6766 and afatinib in H2122.

Fig. 26C shows an exemplary waterfall plot summarizing the combined synergy of VS-6766+ afatinib in a set of KRAS mut NSCLC and PDAC cell lines.

Fig. 27A shows an exemplary graph summarizing the combined synergy of VS-6766+ afatinib in a panel of KRAS mut NSCLC and PDAC cell lines.

FIG. 27B shows exemplary data for a combination of VS-6766 and afatinib showing an increase in anti-tumor response in H2122 cells.

FIG. 28 shows exemplary changes in tumor volume in H2122 tumor-bearing mice treated with VS-6766 (0.3 mg/kg QD) +/-afatinib (10 mg/kg QD).

FIG. 29 shows exemplary changes in tumor volume and survival in H1975 (L858R/T790M) tumor-bearing mice treated with VS-6766 (0.3 mg/kg QD) +/-Ornitinib (2.5 mg/kg QD).

FIG. 30 shows exemplary changes in tumor volume and survival in H1975 octenib drug resistance (Del 19/T790M/C797S) tumor bearing mice treated with VS-6766 (0.3 mg/kg QD) +/-octenib (2.5 mg/kg QD).

Detailed Description

As generally described herein, the present disclosure provides methods and combinations of compounds (e.g., combinations of compounds described herein, e.g., SHP2 inhibitors, SOS1 inhibitors, ERK1/2 inhibitors, CDK4/6 inhibitors, AKT inhibitors, mTOR inhibitors, pan-HER inhibitors, or EGFR inhibitors in combination with MEK inhibitors or dual RAF/MEK inhibitors) that are useful for treating abnormal cell growth (e.g., cancer) in a subject in need thereof.

Definition of the definition

Chemical definition

The definition of specific functional groups and chemical terms is described in more detail below. The chemical elements being CAS according to the periodic Table of the elementsVersion Handbook of Chemistry and Physics, 75 th edition (inner page) and specific functional groups are generally defined as described herein. Furthermore, in Thomas Sorrell, organic Chemistry, university Science Books, sausalato, 1999; smith and March, march's Advanced Organic Chemistry,5 ^th Edition,John Wiley&Sons, inc., new York,2001; larock, comprehensive Organic Transformations, VCH Publishers, inc., new York,1989; and Carruther, some Modern Methods of Organic Synthesis,3 ^rd General principles of organic chemistry, as well as specific functional groups and reactivities, are described in Edition, cambridge University Press, cambridge, 1987.

The compounds described herein may contain one or more asymmetric centers and thus may exist in various isomeric forms, such as enantiomers and/or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. The isomers may be separated from the mixtures by methods known to those skilled in the art, including chiral High Pressure Liquid Chromatography (HPLC) and formation and crystallization of chiral salts; alternatively preferred isomers may be prepared by asymmetric synthesis. See, e.g., jacques et al, entantiomers, racemates and Resolutions (Wiley Interscience, new York, 1981); wilen et al Tetrahedron 33:2725 (1977); eliel, stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, tables of Resolving Agents and Optical Resolutions, page 268 (E.L.Eliel, eds., univ.of Notre Dame Press, notre Dame, IN 1972). The present invention also encompasses the compounds described herein, either as individual isomers substantially free of other isomers, or as mixtures of the various isomers.

As used herein, a pure enantiomeric compound is substantially free of other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, the "S" form of the compound is substantially free of the "R" form of the compound, and thus is in enantiomeric excess of the "R" form. The term "enantiomerically pure" or "pure enantiomer" means that a compound comprises more than 75 wt%, more than 80 wt%, more than 85 wt%, more than 90 wt%, more than 91 wt%, more than 92 wt%, more than 93 wt%, more than 94 wt%, more than 95 wt%, more than 96 wt%, more than 97 wt%, more than 98 wt%, more than 98.5 wt%, more than 99 wt%, more than 99.2 wt%, more than 99.5 wt%, more than 99.6 wt%, more than 99.7 wt%, more than 99.8 wt%, or more than 99.9 wt% of the enantiomer. In some embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

In the compositions provided herein, enantiomerically pure compounds may be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising an enantiomerically pure R-compound may comprise, for example, about 90% excipient and about 10% enantiomerically pure R-compound. In some embodiments, enantiomerically pure R-compounds in such compositions may comprise, for example, at least about 95% by weight of the R-compound and at most about 5% by weight of the S-compound, based on the total weight of the compound. For example, a pharmaceutical composition comprising an enantiomerically pure S-compound may comprise, for example, about 90% excipient and about 10% enantiomerically pure S-compound. In some embodiments, enantiomerically pure S-compounds in such compositions may comprise, for example, at least about 95% by weight of S-compound and at most about 5% by weight of R-compound, based on the total weight of the compounds. In some embodiments, the active ingredient may be formulated with little or no excipients or carriers.

The compounds described herein may also comprise one or more isotopic substitutions. For example, H may be in any isotopic form, including ¹ H、 ² H (D or deuterium) and ³ h (T or tritium); c may be in any isotopic form, including ¹² C、 ¹³ C and C ¹⁴ C, performing operation; o may be in any isotopic form, including ¹⁶ O and ¹⁸ o; f may be in any isotopic form, including ¹⁸ F and F ¹⁹ F, performing the process; etc.

The following terms are intended to have the meanings presented below and to aid in understanding the description and intended scope of the invention. When describing the invention, which may include compounds and pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising such compounds, and methods of using such compounds and compositions, the following terms, if any, have the following meanings, unless otherwise indicated. It will also be understood that when described herein, any of the moieties defined below may be substituted with a variety of substituents, and each definition is intended to include such substituted moieties within the scope thereof as shown below.

The term "halogen atom" as used herein refers to any of the radiostabilizing atoms of column 7 of the periodic table of elements, such as fluorine, chlorine, bromine or iodine, preferably fluorine and chlorine.

The term "ester" as used herein means a compound having the formula- (R) _n -a chemical moiety of COOR ', wherein R and R' are independently selected from: alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), and wherein n is 0 or 1.

The term "amide" as used herein means a compound having the formula- (R) _n -C (O) NHR' or- (R) _n -a chemical moiety of NHC (O) R ', wherein R and R' are independently selected from: alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), and wherein n is 0 or 1. Amides may be amino acid or peptide molecules linked to the molecules of the invention, thereby forming prodrugs.

Any amine, hydroxyl, or carboxyl side chains on the compounds disclosed herein may be esterified or amidated. The manipulation and specific groups for achieving this are known to the person skilled in the art and can be readily found in references such as Greene and Wuts, protective Groups in Organic Synthesis,3 ^rd Ed.,John Wiley&Sons, new York, NY,1999, the entire contents of which are incorporated herein.

The term "aromatic" as used herein refers to an aromatic group having at least one ring with a conjugated pi electron system, and includes both carbocyclic aryl (e.g., phenyl) and heterocyclic aryl (e.g., pyridine). The term includes monocyclic or fused ring polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) groups. The term "carbocycle" refers to a compound containing one or more covalent ring-closing structures and the atoms forming the ring backbone are all carbon atoms. Thus, the term distinguishes carbocycles from heterocycles in which the ring backbone contains at least one atom other than carbon. The term "heteroaromatic" refers to an aromatic group containing at least one heterocyclic ring.

As used herein, "Ca to Cb" (where "a" and "b" are integers) refers to the number of carbon atoms in an alkyl, alkenyl, or alkynyl group, or the number of carbon atoms in a ring of a cycloalkyl, aryl, heteroaryl, or heterocyclyl group. That is, the ring of an alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl group may contain "a" to "b" (inclusive) carbon atoms. Thus, for example, a "C1-C4 alkyl" group or a "C1-C4 alkyl" group means all alkyl groups having 1 to 4 carbons, i.e., CH ₃ -、CH ₃ CH ₂ -、CH ₃ CH ₂ CH ₂ -、(CH ₃ ) ₂ CH-、CH ₃ CH ₂ CH ₂ CH ₂ -、CH ₃ CH ₂ CH(CH ₃ ) -and (CH) ₃ ) ₃ C-. Likewise, for example, a cycloalkyl group may contain a total of "a" to "b" (inclusive) atoms in the ring, e.g., a C3-C8 cycloalkyl group, 3 to 8 carbon atoms. If "a" and "b" are not specified for alkyl, cycloalkyl or cycloalkenyl, then the broadest scope described in these definitions is assumed. Similarly, "4-to 7-membered heterocyclic group" means all heterocyclic groups having a total of 4 to 7 ring atoms, such as azetidine, oxetane, oxazoline, pyrrolidine, piperidine, piperazine, morpholine, and the like. As used herein, the term "C1-C6" includes C1, C2, C3, C4, C5, and C6, as well as ranges defined by any two of the foregoing numbers. For example, C1-C6 alkyl includes C1, C2, C3, C4, C5 and C6 alkyl, C2-C6 alkyl, C1-C3 alkyl, and the like. Similarly, C3-C8 carbocyclyl or cycloalkyl each includes hydrocarbon rings containing 3, 4, 5, 6, 7 and 8 carbon atoms or ranges defined by any two numbers, such as C3-C7 cycloalkyl or C5-C6 cycloalkyl. As another example, a 3 to 10 membered heterocyclyl group includes 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms, or a range defined by any two of the foregoing numbers, e.g., 4 to 6 membered or 5-to 7-membered heterocyclyl.

As used herein, "alkyl" refers to a hydrocarbon group that is fully saturated (without double or triple bonds) with a straight or branched hydrocarbon chain. As used herein, "alkyl" refers to a hydrocarbon group that is fully saturated (without double or triple bonds) with a straight or branched hydrocarbon chain. Alkyl groups may have 1 to 20 carbon atoms (whenever present herein, a numerical range such as "1 to 20" refers to each integer within a given range; e.g., "1 to 20 carbon atoms" refers to an alkyl group that may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term "alkyl", where no numerical range is specified). The alkyl group may also be a medium size alkyl group having 1 to 10 carbon atoms. The alkyl group may also be a lower alkyl group having 1 to 5 carbon atoms. The alkyl group of a compound may be designated as "C1-C4 alkyl" or similar designation. By way of example only, "C1-C4 alkyl" means that there are 1 to 4 carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of: methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, and the like.

Alkyl groups may be substituted or unsubstituted. When substituted, the substituent is one or more groups independently and independently selected from the group consisting of: alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl, heteroaralkyl, (heteroalicyclic) alkyl, hydroxy, protected hydroxy, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxyl, protected C-carboxyl, O-carboxyl, isocyanato, thiocyanato, nitro, silyl, sulfinyl (sulfofinyl), sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido and amino (including mono-and di-substituted amino groups) and protected derivatives thereof. When a substituent is described as "optionally substituted," the substituent may be substituted with one of the substituents described above.

"alkenyl" as used herein refers to an alkyl group containing one or more double bonds in a straight or branched hydrocarbon chain. Alkenyl groups may be unsubstituted or substituted. When substituted, the substituents may be selected from the same groups disclosed above for alkyl substitution. Alkenyl groups may have 2 to 20 carbon atoms, although the present definition also covers the occurrence of the term "alkenyl" where no numerical range is specified. Alkenyl groups may also be medium size alkenyl groups having 2 to 9 carbon atoms. Alkenyl groups may also be lower alkenyl groups having 2 to 4 carbon atoms. Alkenyl groups of compounds may be designated as "C2-C4 alkenyl" or similar designations. By way of example only, "C2-C4 alkenyl" means 2 to 4 carbon atoms in the alkenyl chain, i.e., the alkenyl chain is selected from the group consisting of: vinyl, propen-1-yl, propen-2-yl, propen-3-yl, buten-1-yl, buten-2-yl, buten-3-yl, buten-4-yl, 1-methyl-propen-1-yl, 2-methyl-propen-1-yl, 1-ethyl-ethen-1-yl, 2-methyl-propen-3-yl, but-1, 3-dienyl, but-1, 2-dienyl and but-1, 2-dien-4-yl. Exemplary alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, and the like.

As used herein, "alkynyl" refers to an alkyl group containing one or more triple bonds in a straight or branched hydrocarbon chain. Alkynyl groups may be unsubstituted or substituted. When substituted, the substituents may be selected from the same groups disclosed above for alkyl substitution. Alkynyl groups may have 2 to 20 carbon atoms, although the present definition also covers the occurrence of the term "alkynyl", where no numerical range is specified. Alkynyl groups may also be medium-sized alkynyl groups having 2 to 9 carbon atoms. Alkynyl groups may also be lower alkynyl groups having 2 to 4 carbon atoms. Alkynyl groups of compounds may be designated as "C2-C4 alkynyl" or similar designations. By way of example only, "C2-C4 alkynyl" means that there are 2 to 4 carbon atoms in the alkynyl chain, i.e., the alkynyl chain is selected from the group consisting of: ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-3-yl, butyn-4-yl and 2-butynyl. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

"heteroalkyl" as used herein refers to a straight or branched hydrocarbon chain containing one or more heteroatoms (i.e., elements other than carbon, including but not limited to nitrogen, oxygen, and sulfur) in the backbone. Heteroalkyl groups may have from 1 to 20 carbon atoms, although the present definition also covers the occurrence of the term "heteroalkyl" where no numerical range is specified. The heteroalkyl group may also be a medium size heteroalkyl group having 1 to 9 carbon atoms. The heteroalkyl group may also be a lower heteroalkyl group having 1 to 4 carbon atoms. The heteroalkyl group of a compound may be designated as "C1-C4 heteroalkyl" or a similar designation. The heteroalkyl group may contain one or more heteroatoms. By way of example only, "C1-C4 heteroalkyl" means 1 to 4 carbon atoms in the heteroalkyl chain and an additional heteroatom or heteroatoms in the backbone of the chain.

As used herein, "aryl" refers to a carbocyclic (all carbon) ring or two or more fused rings (rings sharing two adjacent carbon atoms) having a fully delocalized pi-electron system. Examples of aryl groups include, but are not limited to, benzene, naphthalene and azulene. Aryl groups may be substituted or unsubstituted. When substituted, the hydrogen atom is replaced by a substituent, which is one or more groups independently selected from the group consisting of: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl, heteroaralkyl, (heteroalicyclic) alkyl, hydroxy, protected hydroxy, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido and amino (including mono-and di-substituted amino groups) and protected derivatives thereof. When substituted, substituents on the aryl groups can form non-aromatic rings fused to the aryl groups, including cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl.

As used herein, "heteroaryl" refers to a monocyclic or polycyclic aromatic ring system (ring system having a fully delocalized pi electron system), one or two or more fused rings, which contain one or more heteroatoms (i.e., elements other than carbon, including but not limited to nitrogen, oxygen, and sulfur). Examples of heteroaromatic rings include, but are not limited to, furan, thiophene, phthalazine, pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole, triazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, and triazine. Heteroaryl groups may be substituted or unsubstituted. When substituted, the hydrogen atom is replaced by a substituent, which is one or more groups independently selected from the group consisting of: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl, heteroaralkyl, (heteroalicyclic) alkyl, hydroxy, protected hydroxy, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido and amino include mono-and di-substituted amino groups and protected derivatives thereof. When substituted, substituents on heteroaryl groups can form non-aromatic rings fused to aryl groups, including cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl.

As used herein, "aralkyl" or "arylalkyl" refers to an aryl group attached through an alkylene group as a substituent. The alkylene and aryl groups of the aralkyl groups may be substituted or unsubstituted. Examples include, but are not limited to, benzyl, substituted benzyl, 2-phenylethyl, 3-phenylpropyl, and naphthylalkyl. In some cases, the alkylene is a lower alkylene.

As used herein, "heteroarylalkyl" or "heteroarylalkyl" is a heteroaryl group attached through an alkylene group as a substituent. The alkylene and heteroaryl groups of the heteroaralkyl groups may be substituted or unsubstituted. Examples include, but are not limited to, 2-thienylmethyl, 3-thienylmethyl, furylmethyl, thienylethyl, pyrrolidinyl, pyridylalkyl, isoxazolylalkyl, and imidazolylalkyl, and substituted and benzofused analogs thereof. In some cases, the alkylene is a lower alkylene.

As used herein, "alkylene" refers to a branched or straight chain fully saturated diradical chemical group containing only carbon and hydrogen, which is attached to the remainder of the molecule (i.e., an alkanediyl group) through two points of attachment. Alkylene groups may have from 1 to 20 carbon atoms, although the present definition also covers the occurrence of the term alkylene, where no numerical range is specified. The alkylene group may also be a medium size alkylene group having 1 to 9 carbon atoms. The alkylene group may also be a lower alkylene group having 1 to 4 carbon atoms. Alkylene groups may be designated as "C1-C4 alkylene" or similar designations. By way of example only, "C1-C4 alkylene" means having from 1 to 4 carbon atoms in the alkylene chain, i.e., the alkylene chain is selected from the group consisting of: methylene, ethylene-1, 1-diyl, propylene, propane-1, 1-diyl, propane-2, 2-diyl, 1-methyl-ethylene, butylene, butane-1, 1-diyl, butane-2, 2-diyl, 2-methyl-propane-1, 1-diyl, 1-methyl-propylene, 2-methyl-propylene, 1-dimethyl-ethylene, 1, 2-dimethyl-ethylene and 1-ethyl-ethylene.

As used herein, "alkenylene" refers to a straight or branched chain diradical chemical group containing only carbon and hydrogen and containing at least one carbon-carbon double bond attached to the remainder of the molecule through two points of attachment. Alkenylene groups may have 2 to 20 carbon atoms, although the present definition also covers the occurrence of the term alkenylene, where no numerical range is specified. Alkenylene may also be a medium-sized alkenylene having 2 to 9 carbon atoms. Alkenylene may also be lower alkenylene having 2 to 4 carbon atoms. Alkenylene may be designated as "C2-C4 alkenylene" or similar designation. By way of example only, "C2 alkenylene" means that there are 2 to 4 carbon atoms in the alkenylene chain, i.e., the alkenylene chain is selected from the group consisting of: ethylene, ethylene-1, 1-diyl, propylene-1, 1-diyl, prop-2-en-1, 1-diyl, 1-methyl-ethylene, but-1-ylene, but-2-ylene, but-1, 3-dienylene, but-1, 1-diyl, but-1, 3-diene-1, 1-diyl, but-2-en-1, 1-diyl, but-3-en-1, 1-diyl, l-methyl-prop-2-en-1, 1-diyl, 2-methyl-prop-2-en-1, 1-diyl, 1-ethyl-ethylene, 1, 2-dimethyl-ethylene, 1-methyl-propylene, 2-methyl-propylene, 3-methyl-propylene, 2-methyl-propylene-1, 1-diyl and 2, 2-dimethyl-ethylene-1, 1-diyl.

As used herein, "alkylene" refers to a divalent group, e.g., =cr' R ", that is attached to one carbon of another group to form a double bond, alkylene including, but not limited to, methine (=ch ₂ ) And ethylene (=chch) ₃ ). As used herein, "arylalkylene" refers to an alkylene in which R' and R "are aryl groups. The alkylene groups may be substituted or unsubstituted.

As used herein, "alkoxy" refers to the formula-OR, wherein R is an alkyl group as defined above, such as methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, tert-pentyloxy, and the like. Alkoxy groups may be substituted or unsubstituted.

As used herein, "alkylthio" refers to the formula-SR, wherein R is an alkyl group as defined above, such as methyl mercaptan, ethyl mercaptan, n-propyl mercaptan, 1-methyl ethyl mercaptan (isopropyl mercaptan), n-butyl mercaptan, isobutyl mercaptan, sec-butyl mercaptan, tert-butyl mercaptan, and the like. Methyl mercapto group, ethyl mercapto group, n-propyl mercapto group, 1-methyl ethyl mercapto group (isopropyl mercapto group), n-butyl mercapto group, isobutyl mercapto group, sec-butyl mercapto group, tert-butyl mercapto group, and the like. Alkylthio groups may be substituted or unsubstituted.

As used herein, "aryloxy" and "arylthio" refer to RO-and RS-, respectively, wherein R is an aryl group, such as, but not limited to, phenyl. Both aryloxy and arylthio groups may be substituted or unsubstituted.

As used herein, "acyl" refers to-C (=o) R, wherein R is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 carbocyclyl, aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein. Non-limiting examples include formyl, acetyl, propionyl, benzoyl and acryloyl.

As used herein, "cycloalkyl" refers to a fully saturated (non-double bond) mono-or polycyclic hydrocarbon ring system. When composed of two or more rings, the rings may be connected together in a fused, bridged or bolted fashion. Cycloalkyl groups may range from C3 to C10, in other embodiments, they may range from C3 to C6. Cycloalkyl groups may be unsubstituted or substituted. Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. If substituted, unless otherwise indicated, the substituents may be alkyl groups or selected from those indicated above with respect to alkyl substitution. When substituted, substituents on cycloalkyl groups can form aromatic rings fused to cycloalkyl groups, including aryl and heteroaryl groups.

As used herein, "cycloalkenyl" refers to cycloalkyl groups containing one or more double bonds in the ring, but if multiple double bonds are present, they are not able to form a fully delocalized pi-electron system in the ring (otherwise the group would be an "aryl" group, as defined herein). When composed of two or more rings, the rings may be connected together in a fused, bridged or bolted fashion. Cycloalkenyl groups may be unsubstituted or substituted. When substituted, unless otherwise indicated, the substituents may be alkyl or selected from the groups disclosed above for alkyl substitution. When substituted, substituents on the cycloalkenyl group can form aromatic rings fused to the cycloalkenyl group, including aryl and heteroaryl groups.

As used herein, "cycloalkynyl" refers to cycloalkyl groups containing one or more triple bonds in the ring. When composed of two or more rings, the rings may be connected together in a fused, bridged or bolted fashion. The cycloalkynyl group may be unsubstituted or substituted. When substituted, unless otherwise indicated, the substituents may be alkyl or selected from the groups disclosed above for alkyl substitution. When substituted, substituents on the cycloalkynyl group can form an aromatic ring fused to the cycloalkynyl group, including aryl and heteroaryl groups.

As used herein, "heteroalicyclic" or "heteroalicyclic" refers to a stable 3-to 18-membered ring consisting of carbon atoms and 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur. "heteroalicyclic" or "heteroalicyclic" groups may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which may be joined together in a fused, bridged, or spiro-linked manner; and the nitrogen, carbon and sulfur atoms in the "heteroalicyclic" or "heteroalicyclic" group may optionally be oxidized; nitrogen may optionally be quaternized; and the rings may also contain one or more double bonds, provided that they do not form a completely delocalized pi-electron system in all rings. The heteroalicyclic may be unsubstituted or substituted. When substituted, the substituents may be one or more groups independently selected from the group consisting of: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl, heteroaralkyl, (heteroalicyclic) alkyl, hydroxy, protected hydroxy, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, haloalkyl, haloalkoxy, trihalomethylsulfonyl, trihalomethylsulfonylamino, and amino (including mono-and di-substituted amino groups) and protected derivatives thereof. Examples of such "heteroalicyclic" or "heteroalicyclic" include, but are not limited to, azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, morpholinyl, oxiranyl, piperidinyl A-oxide, piperidinyl, piperazinyl, pyrrolidinyl, 4-piperidinyl, pyrazolidinyl, 2-oxopyrrolidinyl, thiomorpholinyl sulfoxide, and thiomorpholinyl sulfone. When substituted, the substituents on the heteroalicyclic group may form an aromatic ring fused to the heteroalicyclic group, including aryl and heteroaryl groups.

As used herein, the term "(cycloalkenyl) alkyl" refers to cycloalkenyl groups linked via an alkylene group as a substituent. The alkylene and cycloalkenyl groups of the (cycloalkenyl) alkyl groups may be substituted or unsubstituted. In some cases, the alkylene is a lower alkylene.

As used herein, the term "(cycloalkynyl) alkyl" refers to a cycloalkynyl group attached via an alkylene group as a substituent. The alkylene groups of the (cycloalkynyl) alkyl groups and the cycloalkynyl groups may be substituted or unsubstituted. In some cases, the alkylene is a lower alkylene.

As used herein, the term "O-carboxy" refers to a "RC (=o) O-group, wherein R may be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl, or (heteroalicyclic) alkyl, as defined herein. The O-carboxy group may be substituted or unsubstituted.

As used herein, the term "C-carboxy" refers to a "-C (=o) R" group, wherein R may be as defined for O-carboxy. The C-carboxyl group may be substituted or unsubstituted.

The term "trihalomethylsulfonyl" as used herein means "X ₃ CSO ₂ - "group wherein X is halogen.

As used herein, the term "cyano" refers to a "-CN" group.

As used herein, the term "cyanooxy" refers to an "-OCN" group.

As used herein, the term "isocyanato" refers to an "-NCO" group.

As used herein, the term "thiocyanic acid" refers to an "-SCN" group.

As used herein, the term "isothiocyanato" refers to an "-NCS" group.

As used herein, the term "sulfinyl" refers to an "-S (=o) -R" group, wherein R may be as defined for the O-carboxy group. Sulfinyl groups may be substituted or unsubstituted.

The term "sulfonyl" as used herein refers to "-SO ₂ R' groups, wherein R may be as defined for the O-carboxyl group. Sulfonyl groups may be substituted or unsubstituted.

The term "S-sulfonylamino", as used herein"means" -SO ₂ NRARB "groups, wherein RA and RB may be as defined for O-carboxy. The S-sulfonylamino group may be substituted or unsubstituted.

The term "N-sulfonylamino" as used herein means "-SO ₂ An N (RA) (RB) "group, wherein RA and RB can be the same as defined for the O-carboxy group. Sulfonyl groups may be substituted or unsubstituted.

The term "trihalomethylsulfonylamino" as used herein means "X ₃ CSO ₂ An N (R) - "group, wherein X is halogen, and R may be as defined for the O-carboxy group. The trihalomethanesulfonylamino group may be substituted or unsubstituted.

As used herein, the term "O-carbamoyl" refers to an "-OC (=o) NRARB" group, wherein RA and RB may be as defined for O-carboxy. The O-carbamoyl group may be substituted or unsubstituted.

As used herein, the term "N-carbamoyl" refers to the "ROC (=o) NRA" group, wherein R and RA may be as defined for O-carboxy. The N-carbamoyl group may be substituted or unsubstituted.

As used herein, the term "O-thiocarbamoyl" refers to an "-OC (=s) -NRARB" group, wherein RA and RB may be as defined for the O-carboxyl group. The O-thiocarbamoyl group may be substituted or unsubstituted.

As used herein, the term "N-thiocarbamoyl" refers to the "ROC (=s) NRA-group, wherein R and RA may be as defined for the O-carboxyl group. The N-thiocarbamoyl group may be substituted or unsubstituted.

As used herein, the term "C-amido" refers to a "-C (=o) NRARB" group, wherein RA and RB may be as defined for O-carboxy. The C-amido group may be substituted or unsubstituted.

As used herein, the term "N-amido" refers to the "RC (=o) NRA-" group, wherein R and RA may be as defined for O-carboxy. The N-amido group may be substituted or unsubstituted.

As used herein, the term "amino" refers to an "-NRARB" group, wherein RA and RB are each independently selected from: hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 carbocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

As used herein, the term "aminoalkyl" refers to an amino group attached through an alkylene group.

As used herein, the term "ester" refers to a "-C (=o) OR" group, wherein R may be as defined for O-carboxy. The esters may be substituted or unsubstituted.

As used herein, the term "lower aminoalkyl" refers to an amino group attached through a lower alkylene group. Lower aminoalkyl groups may be substituted or unsubstituted.

As used herein, the term "lower alkoxyalkyl" refers to an alkoxy group attached through a lower alkylene group. Lower alkoxyalkyl groups may be substituted or unsubstituted.

The term "acetyl" as used herein refers to-C (=o) CH ₃ A group.

As used herein, the term "perhaloalkyl" refers to an alkyl group in which all hydrogen atoms are replaced by halogen atoms.

As used herein, the term "carbocyclyl" refers to a non-aromatic ring or ring system containing only carbon atoms in the ring system backbone. When carbocyclyl is a ring system, two or more rings may be connected together in a fused, bridged or spiro manner. Carbocyclyl groups may have any degree of saturation provided that at least one ring in the ring system is not aromatic. Thus, carbocyclyl includes cycloalkyl, cycloalkenyl, and cycloalkynyl. Carbocyclyl groups may have 3 to 20 carbon atoms, although the present definition also covers the occurrence of the term "carbocyclyl", where no numerical range is specified. The carbocyclyl group may also be a medium size carbocyclyl group having 3 to 10 carbon atoms. The carbocyclyl group may also be a carbocyclyl group having 3 to 6 carbon atoms. Carbocyclyl may be designated as "C3-C6 carbocyclyl" or similar designations. Examples of carbocyclyl rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2, 3-indane, bicyclo [2.2.2] octyl, adamantyl, and spiro [4.4] nonyl.

As used herein, the term "(cycloalkyl) alkyl" refers to cycloalkyl groups attached through an alkylene group as a substituent. The alkylene and cycloalkyl groups of the (cycloalkyl) alkyl groups may be substituted or unsubstituted. Examples include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, and the like. In some cases, the alkylene is a lower alkylene.

As used herein, the term "cycloalkyl" refers to a fully saturated carbocyclyl ring or ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

As used herein, the term "cycloalkenyl" refers to a carbocyclic ring or ring system having at least one double bond, wherein no ring in the ring system is aromatic. One example is cyclohexenyl.

As used herein, the term "heterocyclyl" refers to three-, four-, five-, six-, seven-, and eight-or more membered rings in which the carbon atoms together with 1 to 3 heteroatoms form the ring. However, the heterocyclyl may optionally contain one or more unsaturated bonds that are positioned in a manner that does not result in an aromatic pi-electron system. The heteroatoms are independently selected from oxygen, sulfur, and nitrogen. The heterocyclyl group may also contain one or more carbonyl or thiocarbonyl functional groups, such that definition includes oxo and thio systems, such as lactams, lactones, cyclic imides, cyclic thioimides, cyclic carbamates, and the like. "heterocyclyl" may refer to a non-aromatic ring or ring system containing at least one heteroatom in the ring backbone. The heterocyclic groups may be linked together in a fused, bridged or spiro manner. The heterocyclyl group may have any degree of saturation, provided that at least one ring in the ring system is not aromatic. Heteroatoms may be present in non-aromatic or aromatic rings in the ring system. Heterocyclyl groups may have 3 to 20 ring members (i.e., the number of atoms comprising the ring backbone, including carbon atoms and heteroatoms), although the present definition also covers the occurrence of the term "heterocyclyl" wherein no numerical range is specified. The heterocyclyl may also be a medium sized heterocyclyl having 3 to 10 ring members. The heterocyclyl may also be a heterocyclyl having 3 to 6 ring members. Heterocyclyl groups may be designated as "3-6 membered heterocyclyl" or similar designations. In a preferred six-membered monocyclic heterocyclyl, the heteroatoms are selected from one to three of O, N or S, and in a preferred five-membered monocyclic heterocyclyl, the heteroatoms are selected from one or two of O, N or S. Examples of heterocyclyl rings include, but are not limited to, azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, oxacycloheptyl (oxapanyl), thiepanyl (thiepanyl), piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl, 4-piperidone, pyrazolinyl, pyrazolidinyl, 1, 3-dioxanyl (dioxanyl), 1, 3-dioxanyl, 1, 4-dioxanyl, 1, 3-oxathianyl, 1, 4-oxathiadienyl, 1, 4-oxathianyl, 2// -l, 2-oxazinyl, trioxane (trioxane yl), hexahydro-l, 3, 5-triazinyl, 1, 3-dioxolyl, 1, 3-dithiolane (dithiolyl), 1, 3-dithiolane (dithiolanyl), isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidone, thiazolinyl, thiazolidinyl, 1, 3-oxathiolanyl, indolinyl, isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydro-l, 4-thiazinyl, thiomorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl and tetrahydroquinoline.

As used herein, the term "(heterocyclyl) alkyl" refers to a heterocyclyl attached through an alkylene group as a substituent. Examples include, but are not limited to, imidazolinylmethyl and indolinylethyl.

The substituted group is based on or derived from an unsubstituted parent group in which one or more hydrogen atoms are exchanged with another atom or group. When a group is considered "substituted" unless otherwise indicated, the group is substituted with one or more substituents independently selected from the group consisting of: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C7 carbocyclyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 halo)Alkoxy), C3-C7-carbocyclyl-C1-C6-alkyl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5-10-membered heterocyclyl-C1-C6-alkyl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy) aryl (C1-C6) alkyl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5-to 10-membered heteroaryl (C1-C6) alkyl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), halogen, cyano, hydroxy, C1-C6 alkoxy (C1-C6) alkyl (i.e., ether), aryloxy, mercapto (mercapto), halo (C1-C6) alkyl (e.g. -CF) ₃ ) Halo (C1-C6) alkoxy (e.g. -OCF ₃ ) C1-C6 alkylthio, arylthio, amino (C1-C6) alkyl, nitro, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxyl, O-carboxyl, acyl, cyanooxy, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl and oxo (= O). When a group is described as "optionally substituted," the group may be substituted with the substituents described above.

In some embodiments, a substituted group is substituted with one or more substituents independently and independently selected from the group consisting of: C1-C4 alkyl, amino, hydroxy and halogen.

It should be appreciated that certain radical naming conventions may include single radicals or dual radicals, depending on the context. For example, where a substituent requires two points of attachment to the remainder of the molecule, it is understood that the substituent is a diradical. For example, substituents identified as alkyl groups requiring two points of attachment include bisFree radicals, e.g. -CH ₂ -、-CH ₂ CH ₂ -、-CH ₂ CH(CH ₃ )CH ₂ -and the like. Other radical naming conventions clearly indicate that the radical is a diradical, such as "alkylene" or "alkenylene".

Unless otherwise indicated, when a substituent is considered "optionally substituted" it is meant that the substituent is a group that may be substituted with one or more groups independently and independently selected from: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanic, isothiocyanato, nitro, silyl, trihalomethanesulfonyl and amino (including mono-and di-substituted amino groups) and protected derivatives thereof. Protecting groups that can form protective derivatives of the above substituents are known to those skilled in the art and can be found in references such as Greene and Wuts, described above.

Other definitions

"about" and "approximately" generally mean an acceptable degree of error in the measured quantity taking into account the nature or accuracy of the measurement. Exemplary degrees of error are within 20 percent (%) of a given value or range of values, typically within 10%, more typically within 5%.

As used herein, "pharmaceutically acceptable salts" refers to those salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, berge et al, J.pharmaceutical Sciences (1977) 66: pharmaceutically acceptable salts are described in detail in 1-19. Pharmaceutically acceptable salts of the compounds of the invention include those derived from suitable inorganic and organic acids and bases. Pharmaceutically acceptable non-toxic acid additionExamples of salts are salts of amino groups with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or by using other methods used in the art, for example ion exchange. Other pharmaceutically acceptable salts include adipic acid salts, alginates, ascorbates, aspartic acid salts, benzenesulfonic acid salts, benzoic acid salts, bisulfate salts, boric acid salts, butyric acid salts, camphoric acid salts, citric acid salts, cyclopentanepropionic acid salts, digluconate, dodecylsulfuric acid salts, ethanesulfonic acid salts, formic acid salts, fumaric acid salts, glucoheptonate, glycerophosphate, gluconic acid salts, hemisulfate, heptanoic acid salts, caproic acid salts, hydroiodic acid salts, 2-hydroxy-ethanesulfonic acid salts, lactobionic acid salts, lactic acid salts, lauric acid salts, lauryl sulfuric acid salts, malic acid salts, maleic acid salts, malonic acid salts, methanesulfonic acid salts, 2-naphthalenesulfonic acid salts, nicotinic acid salts, nitrate, oleic acid salts, oxalic acid salts, palmitic acid salts, pamoic acid salts, pectic acid salts, persulfates, 3-phenylpropionic acid salts, phosphates, picrate, pivalic acid salts, propionic acid salts, stearates, succinic acid salts, sulfuric acid salts, tartaric acid salts, thiocyanate salts, p-toluenesulfonic acid salts, undecanoate, valeric acid salts, and the like. Pharmaceutically acceptable salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N ⁺ (C _1–4 Alkyl group ₄ And (3) salt. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Additional pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, where appropriate, formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

As used herein, a "pharmaceutically acceptable carrier" refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

As used herein, a "subject" contemplated for administration includes, but is not limited to, humans (i.e., males or females of any age group, such as pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle aged adults, or elderly) and/or non-human animals, such as mammals, such as primates (e.g., cynomolgus, rhesus), cows, pigs, horses, sheep, goats, rodents, cats, and/or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

Diseases, disorders, and conditions are used interchangeably herein.

As used herein and unless otherwise specified, the terms "treat" (treat, treating and treatment) encompass the effect that occurs when a subject suffers from a specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition or delays or reduces the progression of the disease, disorder or condition (also referred to as "therapeutic treatment").

In general, an "effective amount" of a compound refers to an amount sufficient to elicit the desired biological response. As will be appreciated by those of skill in the art, the effective amount of the compounds of the present invention may vary depending on factors such as: the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, the age, weight, health, and condition of the subject.

As used herein, unless otherwise indicated, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. A therapeutically effective amount of a compound refers to an amount of a therapeutic agent alone or in combination with other therapies that provides a therapeutic benefit in the treatment of a disease, disorder or condition. The term "therapeutically effective amount" may encompass an amount that improves overall treatment, reduces or avoids symptoms or causes of a disease or disorder, or enhances the therapeutic efficacy of another therapeutic agent.

As used herein, "prophylactic treatment" encompasses actions that occur before a subject begins to suffer from a particular disease, disorder, or condition.

As used herein, unless otherwise indicated, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder, or condition, or one or more symptoms associated with a disease, disorder, or condition, or to prevent recurrence thereof. A prophylactically effective amount of a compound refers to an amount of a therapeutic agent alone or in combination with other agents that provides a prophylactic benefit in preventing a disease, disorder, or condition. The term "prophylactically effective amount" may encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

As used herein, the term "oral dosage form" refers to a composition or medium for administration of an agent to a subject. Generally, oral dosage forms are administered orally, however, "oral dosage forms" are intended to encompass any substance that is administered to a subject and absorbed through a membrane of the gastrointestinal tract, such as the mucosa, including, for example, the mouth, esophagus, stomach, small intestine, large intestine, and colon. For example, "oral dosage form" encompasses solutions administered into the stomach through a feeding tube.

As used herein in the context of a drug administration cycle, "cycle" refers to a period of time during which a drug is administered and may further include a rest period during which the drug is not administered to a subject. In some embodiments, 1 cycle is 4 weeks (e.g., three weeks of administration followed by one week of discontinuation).

"KRAS mutations" are mutations in the KRAS gene (i.e., nucleic acid mutations) or KRAS protein (i.e., amino acid mutations) that result in aberrant KRAS protein function associated with increased and/or constitutive activity by favoring the active GTP binding state of KRAS protein. Mutations may be located at conserved sites favoring GTP binding and constitutively active Kras protein. In some cases, the mutation is located at one or more of codons 12, 13 and 16 of the KRAS gene. For example, a KRAS mutation may be at codon 12 of the KRAS gene, e.g., as a single point substitution mutation at codon 12 (i.e., a KRAS G12X mutation) (e.g., a KRAS G12V mutation resulting from a single nucleotide change (c.35G > T) and resulting in substitution of glycine (G) at position 12 with valine (V). Exemplary KRAS G12X mutations include, but are not limited to, KRAS G12V, KRAS G12D, KRAS G12A, KRAS G12R, KRAS G12S, or KRAS G12C.

"RAF mutation" is a mutation in the RAF gene. A "BRAF mutation" is a mutation in the BRAF gene. An "ARAF mutation" is a mutation in the ARAF gene. A "CRAF mutation" is a mutation in the CRAF gene.

Therapeutic method

Combinations of compounds described herein (e.g., SHP2 inhibitors, SOS1 inhibitors, ERK1/2 inhibitors, CDK4/6 inhibitors, AKT inhibitors, mTOR inhibitors, pan-HER inhibitors, or EGFR inhibitors in combination with MEK inhibitors or dual RAF/MEK inhibitors) and pharmaceutical compositions thereof are generally useful in methods of treating abnormal cell growth such as cancer.

Accordingly, in one aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a combination of an SHP2 inhibitor and a MEK inhibitor, thereby treating the subject. In some embodiments, the method further comprises administering an additional agent.

In another aspect, disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a combination of an SHP2 inhibitor and a dual RAF/MEK inhibitor (e.g., VS-6766), thereby treating the subject. In some embodiments, the method further comprises administering an additional agent.

In some embodiments of the methods described herein, the duration of response to an SHP2 inhibitor may be reduced by administering to a subject in need thereof a combination of an SHP2 inhibitor and a MEK inhibitor. In some embodiments, the duration of response to an SHP2 inhibitor may be reduced by administering to a subject in need thereof a combination of an SHP2 inhibitor and a RAF/MEK inhibitor (e.g., VS-6766). In some embodiments, the combinations described herein can improve the depth and/or duration of a response (e.g., an anti-tumor response) in a subject.

The contemplated subjects of the methods described herein can be identified (e.g., by screening, e.g., sequencing) as having SHP2 mutations.

The methods disclosed herein also contemplate treating a subject identified as having a KRAS mutation (e.g., a KRAS G12X mutation (e.g., KRAS G12V, KRAS G12D, KRAS G12A, KRAS G12R, KRAS G12S, or KRAS G12C)) by administering a MEK inhibitor in combination with a SHP2 inhibitor, optionally with an additional agent, to the subject.

The methods disclosed herein also contemplate treating a subject identified as having a KRAS mutation (e.g., KRAS G12V, KRAS G12D, KRAS G12A, KRAS G12R, KRAS G12S, or KRAS G12C) by administering to the subject a dual RAF/MEK inhibitor (e.g., VS-6766) in combination with a SHP2 inhibitor, optionally with an additional agent.

In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a combination of a SOS1 inhibitor and a MEK inhibitor, thereby treating the subject. In some embodiments, the method further comprises administering an additional agent.

In another aspect, disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a SOS1 inhibitor in combination with a dual RAF/MEK inhibitor (e.g., VS-6766), thereby treating the subject. In some embodiments, the method further comprises administering an additional agent.

In some embodiments of the methods described herein, the duration of response to a SOS1 inhibitor may be reduced by administering a combination of a SOS1 inhibitor and a MEK inhibitor to a subject in need thereof. In some embodiments, the duration of response to a SOS1 inhibitor may be reduced by administering to a subject in need thereof a combination of a SOS1 inhibitor and a RAF/MEK inhibitor (e.g., VS-6766). In some embodiments, the combinations described herein can improve the depth and/or duration of a response (e.g., an anti-tumor response) in a subject.

The contemplated subject of the methods described herein can be identified (e.g., by screening, e.g., sequencing) as having SOS1 mutations.

The methods disclosed herein also contemplate treating a subject identified as having a KRAS mutation (e.g., a KRAS G12X mutation (e.g., KRAS G12V, KRAS G12D, KRAS G12A, KRAS G12R, KRAS G12S, or KRAS G12C)) by administering a MEK inhibitor in combination with a SOS1 inhibitor, optionally with an additional agent, to the subject.

The methods disclosed herein also contemplate treating a subject identified as having a KRAS mutation (e.g., KRAS G12V, KRAS G12D, KRAS G12A, KRAS G12R, KRAS G12S, or KRAS G12C) by administering to the subject a dual RAF/MEK inhibitor (e.g., VS-6766) in combination with an SOS1 inhibitor, optionally with an additional agent.

In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a combination of an ERK1/2 inhibitor and a MEK inhibitor, thereby treating the subject. In some embodiments, the method further comprises administering an additional agent.

In another aspect, disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a combination of an ERK1/2 inhibitor and a dual RAF/MEK inhibitor (e.g., VS-6766), thereby treating the subject. In some embodiments, the method further comprises administering an additional agent.

In some embodiments of the methods described herein, the duration of response to an ERK1/2 inhibitor may be reduced by administering to a subject in need thereof a combination of an ERK1/2 inhibitor and a MEK inhibitor. In some embodiments, the duration of response to an ERK1/2 inhibitor may be shortened by administering to a subject in need thereof a combination of an ERK1/2 inhibitor and a RAF/MEK inhibitor (e.g., VS-6766). In some embodiments, the combinations described herein can improve the depth and/or duration of a response (e.g., an anti-tumor response) in a subject.

Contemplated subjects of the methods described herein can be identified (e.g., by screening, e.g., sequencing) as having an ERK1/2 mutation.

The methods disclosed herein also contemplate treating a subject identified as having a KRAS mutation (e.g., a KRAS G12X mutation (e.g., KRAS G12V, KRAS G12D, KRAS G12A, KRAS G12R, KRAS G12S, or KRAS G12C)) by administering a MEK inhibitor in combination with an ERK1/2 inhibitor, optionally with an additional agent, to the subject.

The methods disclosed herein also contemplate treating a subject identified as having a KRAS mutation (e.g., KRAS G12V, KRAS G12D, KRAS G12A, KRAS G12R, KRAS G12S, or KRAS G12C) by administering to the subject a dual RAF/MEK inhibitor (e.g., VS-6766) in combination with an ERK1/2 inhibitor, optionally with an additional agent.

In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a CDK4/6 inhibitor in combination with a MEK inhibitor, thereby treating the subject. In some embodiments, the method further comprises administering an additional agent.

In another aspect, disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a CDK4/6 inhibitor in combination with a dual RAF/MEK inhibitor (e.g., VS-6766) or a pharmaceutically acceptable salt thereof, thereby treating the subject. In some embodiments, the method further comprises administering an additional agent.

In some embodiments of the methods described herein, the duration of response to a CDK4/6 inhibitor may be reduced by administering to a subject in need thereof a combination of a CDK4/6 inhibitor and a MEK inhibitor. In some embodiments, the duration of response to a CDK4/6 inhibitor may be shortened by administering to a subject in need thereof a combination of a CDK4/6 inhibitor and a RAF/MEK inhibitor (e.g., VS-6766). In some embodiments, the combinations described herein can improve the depth and/or duration of a response (e.g., an anti-tumor response) in a subject.

Contemplated subjects of the methods described herein may be identified (e.g., by screening, e.g., sequencing) as having CDK4/6 mutations.

The methods disclosed herein also contemplate treating a subject identified as having a KRAS mutation (e.g., a KRAS G12X mutation (e.g., KRAS G12V, KRAS G12D, KRAS G12A, KRAS G12R, KRAS G12S, or KRAS G12C)) by administering a MEK inhibitor in combination with a CDK4/6 inhibitor, optionally with an additional agent, to the subject.

The methods disclosed herein also contemplate treating a subject identified as having a KRAS mutation (e.g., KRAS G12V, KRAS G12D, KRAS G12A, KRAS G12R, KRAS G12S, or KRAS G12C) by administering to the subject a dual RAF/MEK inhibitor (e.g., VS-6766) in combination with a CDK4/6 inhibitor, optionally with an additional agent.

In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a combination of an AKT inhibitor and a MEK inhibitor, thereby treating the subject. In some embodiments, the method further comprises administering an additional agent.

In another aspect, disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a combination of an AKT inhibitor and a dual RAF/MEK inhibitor (e.g., VS-6766), thereby treating the subject. In some embodiments, the method further comprises administering an additional agent.

In some embodiments of the methods described herein, the duration of response to an AKT inhibitor may be reduced by administering to a subject in need thereof a combination of an AKT inhibitor and a MEK inhibitor. In some embodiments, the duration of response to an AKT inhibitor may be shortened by administering to a subject in need thereof a combination of an AKT inhibitor and a RAF/MEK inhibitor (e.g., VS-6766). In some embodiments, the combinations described herein can improve the depth and/or duration of a response (e.g., an anti-tumor response) in a subject.

The contemplated subjects of the methods described herein can be identified (e.g., by screening, e.g., sequencing) as having AKT mutations.

The methods disclosed herein also contemplate treating a subject identified as having a KRAS mutation (e.g., a KRAS G12X mutation (e.g., KRAS G12V, KRAS G12D, KRAS G12A, KRAS G12R, KRAS G12S, or KRAS G12C)) by administering a MEK inhibitor in combination with an AKT inhibitor, optionally with an additional agent, to the subject.

The methods disclosed herein also contemplate treating a subject identified as having a KRAS mutation (e.g., KRAS G12V, KRAS G12D, KRAS G12A, KRAS G12R, KRAS G12S, or KRAS G12C) by administering a dual RAF/MEK inhibitor (e.g., VS-6766) in combination with an AKT inhibitor, optionally with an additional agent, to the subject.

In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a combination of an mTOR inhibitor and a MEK inhibitor, thereby treating the subject. In some embodiments, the method further comprises administering an additional agent.

In another aspect, disclosed herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject a mTOR inhibitor in combination with a dual RAF/MEK inhibitor (e.g., VS-6766) or a pharmaceutically acceptable salt thereof, thereby treating the subject. In some embodiments, the method further comprises administering an additional agent.

In some embodiments of the methods described herein, the duration of response to an mTOR inhibitor may be reduced by administering to a subject in need thereof a combination of an mTOR inhibitor and a MEK inhibitor. In some embodiments, the duration of response to an mTOR inhibitor may be reduced by administering to a subject in need thereof a combination of an mTOR inhibitor and a RAF/MEK inhibitor (e.g., VS-6766). In some embodiments, the combinations described herein can improve the depth and/or duration of a response (e.g., an anti-tumor response) in a subject.

The contemplated subjects of the methods described herein can be identified (e.g., by screening, e.g., sequencing) as having an mTOR mutation.

The methods disclosed herein also contemplate treating a subject identified as having a KRAS mutation (e.g., a KRAS G12X mutation (e.g., KRAS G12V, KRAS G12D, KRAS G12A, KRAS G12R, KRAS G12S, or KRAS G12C)) by administering a MEK inhibitor in combination with an mTOR inhibitor, optionally with an additional agent, to the subject.

The methods disclosed herein also contemplate treating a subject identified as having a KRAS mutation (e.g., KRAS G12V, KRAS G12D, KRAS G12A, KRAS G12R, KRAS G12S, or KRAS G12C) by administering to the subject a dual RAF/MEK inhibitor (e.g., VS-6766) in combination with an mTOR inhibitor, optionally with an additional agent.

In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a combination of a pan-HER inhibitor and a MEK inhibitor, thereby treating the subject. In some embodiments, the method further comprises administering an additional agent.

In another aspect, disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a pan-HER inhibitor in combination with a dual RAF/MEK inhibitor (e.g., VS-6766) or a pharmaceutically acceptable salt thereof, thereby treating the subject. In some embodiments, the method further comprises administering an additional agent.

In some embodiments of the methods described herein, the duration of response to a pan-HER inhibitor may be reduced by administering to a subject in need thereof a combination of a pan-HER inhibitor and a MEK inhibitor. In some embodiments, the duration of response to a pan-HER inhibitor may be shortened by administering to a subject in need thereof a combination of a pan-HER inhibitor and a RAF/MEK inhibitor (e.g., VS-6766). In some embodiments, the combinations described herein can improve the depth and/or duration of a response (e.g., an anti-tumor response) in a subject.

The contemplated subject of the methods described herein can be identified (e.g., by screening, e.g., sequencing) as having a pan-HER mutation.

The methods disclosed herein also contemplate treating a subject identified as having a KRAS mutation (e.g., a KRAS G12X mutation (e.g., KRAS G12V, KRAS G12D, KRAS G12A, KRAS G12R, KRAS G12S, or KRAS G12C)) by administering a MEK inhibitor in combination with a pan-HER inhibitor, optionally with an additional agent, to the subject.

The methods disclosed herein also contemplate treating a subject identified as having a KRAS mutation (e.g., KRAS G12V, KRAS G12D, KRAS G12A, KRAS G12R, KRAS G12S, or KRAS G12C) by administering a dual RAF/MEK inhibitor (e.g., VS-6766) in combination with a pan-HER inhibitor, optionally with an additional agent, to the subject.

In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a combination of an EGFR inhibitor and a MEK inhibitor, or a pharmaceutically acceptable salt thereof, thereby treating the subject. In some embodiments, the method further comprises administering an additional agent.

In another aspect, disclosed herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject an EGFR inhibitor in combination with a dual RAF/MEK inhibitor (e.g., VS-6766) or a pharmaceutically acceptable salt thereof, thereby treating the subject. In some embodiments, the method further comprises administering an additional agent.

In some embodiments of the methods described herein, the duration of response to an EGFR inhibitor can be reduced by administering to a subject in need thereof a combination of an EGFR inhibitor and a MEK inhibitor. In some embodiments, the duration of response to an EGFR inhibitor can be reduced by administering to a subject in need thereof a combination of an EGFR inhibitor and a RAF/MEK inhibitor (e.g., VS-6766). In some embodiments, the combinations described herein can improve the depth and/or duration of a response (e.g., an anti-tumor response) in a subject.

The contemplated subjects of the methods described herein can be identified (e.g., by screening, e.g., sequencing) as having EGFR mutations.

The methods disclosed herein also contemplate treating a subject identified as having a KRAS mutation (e.g., a KRAS G12X mutation (e.g., KRAS G12V, KRAS G12D, KRAS G12A, KRAS G12R, KRAS G12S, or KRAS G12C)) by administering a MEK inhibitor in combination with an EGFR inhibitor, optionally with an additional agent, to the subject.

The methods disclosed herein also contemplate treating a subject identified as having a KRAS mutation (e.g., KRAS G12V, KRAS G12D, KRAS G12A, KRAS G12R, KRAS G12S, or KRAS G12C) by administering a dual RAF/MEK inhibitor (e.g., VS-6766) in combination with an EGFR inhibitor, optionally with an additional agent, to the subject.

Src homologous phosphatase 2 (SHP 2) inhibitors

Examples of SHP2 inhibitors include, but are not limited to:

TNO-155 (Novartis AG) having the following structure:

SHP099 having the structure:

RMC-4630 (Revolution Medicines) having the structure:

RMC-4550 (Revolution Medicines) having the structure:

IACS-13909 having the structure:

JAB-3068 (Jacobio Pharmaceuticals Co Ltd) having the structure:

JAB-3312 (Jacobio Pharmaceuticals Co Ltd); RLY-1971 (Relay Therapeutics Inc); BBP-398 (Navire Pharma Inc); ERAS-601 (ERASCA); HBI-2376 (HUYA Bioscience International LLC); ICP-189 (InnoCare Pharma Ltd), BR790 (Shanghai Blueray Biopharma); ETS-001 (Shanghai ETERN Biopharma); PF-07284892 (Pfizer); RX-SHP2i (Redx Pharma); SH3809 (Nanjing Sanhome Pharmaceutical); TAS-ASTX (Taiho Oncology); X-37-SHP2 (X-37); and hydrates, solvates and pharmaceutically acceptable salts thereof.

In some embodiments, the SHP2 inhibitor is ERAS-601, TNO-155, SHP099, RMC-4630, RMC-4550, IACS-13909, JAB-3068, JAB-3312, RLY-1971, BBP-398, HBI-2376, or ICP-189, or a hydrate, solvate, or pharmaceutically acceptable salt thereof.

In some embodiments, the SHP2 inhibitor is ERAS-601, JAB-3068, RMC-4630, TNO-155, JAB-3312, RLY-1971, BBP-398, HBI-2376, ICP-189 or RMC-4550, or a hydrate, solvate or pharmaceutically acceptable salt thereof.

In some embodiments, the SHP2 inhibitor is administered at least once a week. In some embodiments, the SHP2 inhibitor is administered at least once a day. In some embodiments, the SHP2 inhibitor is administered once daily. In some embodiments, the SHP2 inhibitor is administered twice daily. In some embodiments, the SHP2 inhibitor is administered orally.

In some embodiments, the SHP2 inhibitor is administered at a dose of about 0.1mg to about 5000mg, e.g., about 1mg to about 3000mg, about 1mg to about 1000mg, about 1mg to about 500mg, about 1mg to about 100mg, about 10mg to about 2000mg, e.g., about 100mg to about 2000mg, about 100mg to about 1500mg, about 100mg to about 1000mg, about 100mg to about 800mg, about 100mg to about 600mg, about 100mg to about 400mg, about 100mg to about 200mg, about 200mg to about 2000mg, about 200mg to about 1500mg, about 200mg to about 1000mg, about 200mg to about 800mg, about 200mg to about 600mg, about 200mg to about 400mg, about 400mg to about 2000mg, about 400mg to about 1500mg, about 400mg to about 1000mg, about 400mg to about 800mg, about 400mg to about 600mg, about 600mg to about 2000mg, about 600mg to about 1500mg, about 600mg to about 1000mg, about 600mg to about 800mg, about 800mg to about 2000mg, about 800mg to about 1500mg, about 800mg to about 1000mg, about 600mg to about 2000mg, about 600mg to about 1500mg, about 600mg to about 1000mg, about 600mg to about 800 mg. In some embodiments, the SHP2 inhibitor is administered at about 1mg per administration. In some embodiments, the SHP2 inhibitor is administered at about 5mg per administration. In some embodiments, the SHP2 inhibitor is administered at about 10mg per administration. In some embodiments, the SHP2 inhibitor is administered at about 50mg per administration. In some embodiments, the SHP2 inhibitor is administered at about 100mg per administration. In some embodiments, the SHP2 inhibitor is administered at about 200mg per administration. In some embodiments, the SHP2 inhibitor is administered at about 300mg per administration. In some embodiments, the SHP2 inhibitor is administered at about 400mg per administration. In some embodiments, the SHP2 inhibitor is administered at about 500mg per administration. In some embodiments, the SHP2 inhibitor is administered at about 600mg per administration. In some embodiments, the SHP2 inhibitor is administered at about 700mg per administration. In some embodiments, the SHP2 inhibitor is administered at about 800mg per administration. In some embodiments, the SHP2 inhibitor is administered at about 900mg per administration. In some embodiments, the SHP2 inhibitor is administered at about 1000mg per administration.

SOS1 inhibitors

Examples of SOS1 inhibitors include, but are not limited to:

BI-3406 having the structure:

BAY-293 having the structure:

RMC-5845(Revolution Medicines)；SDGR-5(Schrodinger LLC)；BI-1701963(Boehringer Ingleheim)；BMS-SCHand SDGR 5->And hydrates, solvates and pharmaceutically acceptable salts thereof.

In some embodiments, the SOS1 inhibitor is BI-3406, BAY-293, RMC-5845 (Revolution Medicines), SDGR-5 (Schrodinger LLC) or BI-1701963 (Boehringer Ingleheim), or a hydrate, solvate, or pharmaceutically acceptable salt thereof.

In some embodiments, the SOS1 inhibitor is SDGR-5 (Schrodinger LLC) or BI-1701963 (Boehringer Ingleheim), or a hydrate, solvate, or pharmaceutically acceptable salt thereof.

In some embodiments, the SOS1 inhibitor is administered at least once a week. In some embodiments, the SOS1 inhibitor is administered at least once daily. In some embodiments, the SOS1 inhibitor is administered once daily. In some embodiments, the SOS1 inhibitor is administered twice daily. In some embodiments, the SOS1 inhibitor is administered orally.

In some embodiments, the SOS1 inhibitor is administered at a dose of about 0.1mg to about 5000mg, e.g., about 1mg to about 3000mg, about 1mg to about 1000mg, about 1mg to about 500mg, about 1mg to about 100mg, about 10mg to about 2000mg, e.g., about 100mg to about 2000mg, about 100mg to about 1500mg, about 100mg to about 1000mg, about 100mg to about 800mg, about 100mg to about 600mg, about 100mg to about 400mg, about 100mg to about 200mg, about 200mg to about 2000mg, about 200mg to about 1500mg, about 200mg to about 1000mg, about 200mg to about 800mg, about 200mg to about 600mg, about 200mg to about 400mg, about 400mg to about 2000mg, about 400mg to about 1500mg, about 400mg to about 1000mg, about 400mg to about 800mg, about 400mg to about 600mg, about 600mg to about 2000mg, about 600mg to about 1500mg, about 600mg to about 1000mg, about 600mg to about 800mg, about 800mg to about 2000mg, about 800mg to about 1500mg, about 800mg to about 1000mg, about 600mg to about 2000mg, about 600mg to about 1500mg, about 600mg to about 1000mg, about 600mg to about 800 mg. In some embodiments, the SOS1 inhibitor is administered at about 1mg per administration. In some embodiments, the SOS1 inhibitor is administered at about 5mg per administration. In some embodiments, the SOS1 inhibitor is administered at about 10mg per administration. In some embodiments, the SOS1 inhibitor is administered at about 50mg per administration. In some embodiments, the SOS1 inhibitor is administered at about 100mg per administration. In some embodiments, the SOS1 inhibitor is administered at about 200mg per administration. In some embodiments, the SOS1 inhibitor is administered at about 300mg per administration. In some embodiments, the SOS1 inhibitor is administered at about 400mg per administration. In some embodiments, the SOS1 inhibitor is administered at about 500mg per administration. In some embodiments, the SOS1 inhibitor is administered at about 600mg per administration. In some embodiments, the SOS1 inhibitor is administered at about 700mg per administration. In some embodiments, the SOS1 inhibitor is administered at about 800mg per administration. In some embodiments, the SOS1 inhibitor is administered at about 900mg per administration. In some embodiments, the SOS1 inhibitor is administered at about 1000mg per administration.

ERK1/2 inhibitors

Examples of ERK1/2 inhibitors include, but are not limited to:

ASTX-029 (Astex Pharmaceuticals) having the following structure:

LY-3214996 (Eli Lilly and Co) having the structure:

ulitinib (ulixertiinib) having the structure:

ASN-007 (Asana Biosciences) having the structure:

ATG-017 (Antegene Corp) having the following structure:

MK-8353 (Merck) having the structure:

ravoxertiinib having the structure:

AZ6197 (AstraZeneca) having the structure:

BPI-27336 (Betta Pharmaceuticals Co Ltd); JSI-1187 (JS InnoPharm Ltd); HH-2710 (Shanghai Haihe Biopharma Co Ltd); JRP-890 (Prous Institute for Biomedical Research SA); JRF-108 (Chengdu Jinrui Foundation Biotechnology Co Ltd); BI ERKi (Boehringer Ingelheim); CC-90003 (BMS); ERAS-007 (Erasca); HMPL-295 (Hutchmed); IPN-ERK (Ipsen); KO-947 (Kura Oncology); LTT462 (Novartis); SCH772984 (Astex Pharmaceuticals); TK216 (Oncternal Therapeutics), and hydrates, solvates and pharmaceutically acceptable salts thereof.

In some embodiments, the ERK1/2 inhibitor is ASTX-029 (Astex Pharmaceuticals), HH-2710 (Shanghai Haihe Biopharma Co Ltd), LY-3214996 (Eli Lilly and Co), ulitinib, ASN-007 (Asana BioSciences), ATG-017 (Antegene Corp), BPI-27336 (Betta Pharmaceuticals Co Ltd), JSI-1187 (JS Innovarm Ltd, shanghai), MK-8353 (Merck), JRP-890 (Prous Institute for Biomedical Research SA), JRF-108 (Chengdu Jinrui Foundation Biotechnology Co Ltd), or ravoxertinib, or a hydrate, solvate, or pharmaceutically acceptable salt thereof.

In some embodiments, the ERK1/2 inhibitor is administered at least once a week. In some embodiments, the ERK1/2 inhibitor is administered at least once daily. In some embodiments, the ERK1/2 inhibitor is administered once daily. In some embodiments, the ERK1/2 inhibitor is administered twice daily. In some embodiments, the ERK1/2 inhibitor is administered orally.

In some embodiments, the ERK1/2 inhibitor is administered at about 0.1mg to about 5000mg, e.g., about 1mg to about 3000mg, about 1mg to about 1000mg, about 1mg to about 500mg, about 1mg to about 100mg, about 10mg to about 2000mg, e.g., about 100mg to about 2000mg, about 100mg to about 1500mg, about 100mg to about 1000mg, about 100mg to about 800mg, about 100mg to about 600mg, about 100mg to about 400mg, about 100mg to about 200mg, about 200mg to about 2000mg, about 200mg to about 1500mg, about 200mg to about 1000mg, about 200mg to about 800mg, about 200mg to about 600mg, about 200mg to about 400mg, about 400mg to about 2000mg, about 400mg to about 1500mg, about 400mg to about 400mg, about 400mg to about 800mg, about 400mg to about 600mg, about 600mg to about 2000mg, about 1500mg to about 600mg, about 600mg to about 600mg, about 1500mg to about 600mg, about 600mg to about 800mg, about 600mg, about 1500mg to about 600mg, about 600mg to about 600 mg. In some embodiments, the ERK1/2 inhibitor is administered at about 1mg per administration. In some embodiments, the ERK1/2 inhibitor is administered at about 5mg per administration. In some embodiments, the ERK1/2 inhibitor is administered at about 10mg per administration. In some embodiments, the ERK1/2 inhibitor is administered at about 50mg per administration. In some embodiments, the ERK1/2 inhibitor is administered at about 100mg per administration. In some embodiments, the ERK1/2 inhibitor is administered at about 200mg per administration. In some embodiments, the ERK1/2 inhibitor is administered at about 300mg per administration. In some embodiments, the ERK1/2 inhibitor is administered at about 400mg per administration. In some embodiments, the ERK1/2 inhibitor is administered at about 500mg per administration. In some embodiments, the ERK1/2 inhibitor is administered at about 600mg per administration. In some embodiments, the ERK1/2 inhibitor is administered at about 700mg per administration. In some embodiments, the ERK1/2 inhibitor is administered at about 800mg per administration. In some embodiments, the ERK1/2 inhibitor is administered at about 900mg per administration. In some embodiments, the ERK1/2 inhibitor is administered at about 1000mg per administration.

CDK4/6 inhibitors

Examples of CDK4/6 inhibitors include, but are not limited to:

palbociclib (Palbociclib) having the structure:

rebamacinib (Ribociclib) having the structure:

abemaciclib (Abemaciclib) having the structure:

SHR-6390 (Jiangsu Hengrui Medicine Co Ltd) having the structure:

luo Xili (Lerociclib) having the following structure:

azoxystrobin (Milciclib) having the following structure:

PF-06873600 (Pfizer Inc) having the following structure:

ON-123300 (HanX Biopharmaceuticals Inc) having the structure:

SRX-3177 (SignalRx Pharmaceuticals Inc) having the structure:

roniciclib (Bayer) having the following structure:

RMC-4550 (Revolution Medicines Inc) having the structure:

GLR-2007 (Gan and Lee Pharmaceuticals); RP-CDK4/6 (Rhizen Pharmaceuticals); TQB 3303 (Chia Tai Tianqing Pharmaceutical); troracilli (trilacillib) (G1 Therapeutics); FCN-437c (Fochon Pharmaceutical Ltd); XZP-3287 (Sihuan Pharmaceutical Holdings Group Ltd); BEBT-209 (Guangzhou BeBetter Medicine Technology Co Ltd); BPI-16350 (Betta Pharmaceuticals Co Ltd); CS-3002 (CStone Pharmaceuticals Co Ltd); HS-10342 (Jiangsu Hansoh Pharmaceutical Group Co Ltd); TY-302 (Tetranov International Inc); voruciclib; BPI-1178 (Beta Pharma Inc.); NUV-422 (nuchange Bio Inc); AU-294 (Aucentra Therapeutics Pty Ltd); ETH-155008 (Shengke Pharmaceuticals Ltd, jiangsu); HEC-80797 (HEC Pharm Co Ltd); JS-104 (Rizen Biosciences Co Ltd, suzhou); PF-07220060 (Pfizer Inc.); and VS-2370 (ViroStatics srl), and hydrates, solvates and pharmaceutically acceptable salts thereof.

In some embodiments, the CDK4/6 inhibitor is SHR-6390, FCN-437c, lai Luo Xili, azoxystrobin, PF-06873600, XZP-3287, BEBT-209, BPI-16350, CS-3002, HS-10342, ON-123300, TY-302, voruciclib, BPI-1178, NUV-422, AU-294, ETH-155008, HEC-80797, JS-104, PF-07220060, RMC-4550, SRX-3177, VS-2370, palbociclib, rabociclib succinate (e.g., rabociclib succinate), letrozole+Rabociclib succinate, or a solvate, hydrate, or pharmaceutically acceptable salt thereof.

In some embodiments, the CDK4/6 inhibitor is ETH-155008, HEC-80797, JS-104, PF-07220060, RMC-4550, SRX-3177, VS-2370, palbociclib, rebabociclib (e.g., rebabociclib succinate), letrozole+rebabociclib succinate, or arbicimide, or a solvate, hydrate, or pharmaceutically acceptable salt thereof.

In some embodiments, the CDK4/6 inhibitor is administered at least once a week. In some embodiments, the CDK4/6 inhibitor is administered at least once daily. In some embodiments, the CDK4/6 inhibitor is administered once daily. In some embodiments, the CDK4/6 inhibitor is administered twice daily. In some embodiments, the CDK4/6 inhibitor is administered orally.

In some embodiments, the CDK4/6 inhibitor is administered at a dose of about 0.1mg to about 5000mg, e.g., about 1mg to about 3000mg, about 1mg to about 1000mg, about 1mg to about 500mg, about 1mg to about 100mg, about 10mg to about 2000mg, e.g., about 100mg to about 2000mg, about 100mg to about 1500mg, about 100mg to about 1000mg, about 100mg to about 800mg, about 100mg to about 600mg, about 100mg to about 400mg, about 100mg to about 200mg, about 200mg to about 2000mg, about 200mg to about 1500mg, about 200mg to about 1000mg, about 200mg to about 800mg, about 200mg to about 600mg, about 200mg to about 400mg, about 400mg to about 2000mg, about 400mg to about 1500mg, about 400mg to about 1000mg, about 400mg to about 800mg, about 400mg to about 600mg, about 600mg to about 2000mg, about 600mg to about 1500mg, about 600mg to about 1000mg, about 600mg to about 800mg, about 800mg to about 2000mg, about 800mg to about 1500mg, about 800mg to about 1000mg, about 600mg to about 2000mg, about 600mg to about 1500mg, about 600mg to about 1000mg, about 600mg to about 800 mg. In some embodiments, the CDK4/6 inhibitor is administered at about 1mg per administration. In some embodiments, the CDK4/6 inhibitor is administered at about 5mg per administration. In some embodiments, the CDK4/6 inhibitor is administered at about 10mg per administration. In some embodiments, the CDK4/6 inhibitor is administered at about 50mg per administration. In some embodiments, the CDK4/6 inhibitor is administered at about 100mg per administration. In some embodiments, the CDK4/6 inhibitor is administered at about 200mg per administration. In some embodiments, the CDK4/6 inhibitor is administered at about 300mg per administration. In some embodiments, the CDK4/6 inhibitor is administered at about 400mg per administration. In some embodiments, the CDK4/6 inhibitor is administered at about 500mg per administration. In some embodiments, the CDK4/6 inhibitor is administered at about 600mg per administration. In some embodiments, the CDK4/6 inhibitor is administered at about 700mg per administration. In some embodiments, the CDK4/6 inhibitor is administered at about 800mg per administration. In some embodiments, the CDK4/6 inhibitor is administered at about 900mg per administration. In some embodiments, the CDK4/6 inhibitor is administered at about 1000mg per administration.

AKT inhibitors

Examples of AKT inhibitors include, but are not limited to:

capigaservib; patadine; afuresertib hydrochloride; miransertib mesylate; qu Meiti Nidimethyl sulfoxide+Youpultib (uprosisertib); euthane color; borussertib; LY-2503029 (Eli Lilly and Co); COTI-2 (Cotinga Pharmaceuticals Inc); MK-2206+semetinib sulfate (Merck & Co Inc.); PTX-200 (Prescient Therapeutics Ltd); ARQ-751 (Vevorisertib, merck & Co Inc.); ALM-301 (Almac Discovery Ltd); DC-120 (Guangzhou Institute of Biomedicine and Health); FXY-1 (Krisani Bio Sciences Pvt Ltd); JRP-890 (Prous Institute for Biomedical Research SA); KS-99 (Pennsylvania State University); NISC-6 (Pennsylvania State University); RX-0201 (Zhejiang Haichang Biotechnology Co Ltd); RX-0301 (Zhejiang Haichang Biotechnology Co Ltd);

m2698 (Merck) having the following structure:

MK-2206 (Merck & Co Inc) has the following structure:

ONC-201 (Ohara Pharmaceutical Co Ltd) having the structure:

TAS-117 (Taiho Pharmaceutical Co Ltd) having the structure:

AT-13148 (Astex Pharmaceuticals Inc) having the structure:

BAY-1125976 (Bayer AG) having the structure:

and

GSK690693 having the structure:

and hydrates, solvates and pharmaceutically acceptable salts thereof.

In some embodiments, the AKT inhibitor is capigaservib, pataserib, LY-2503029, afuresertib hydrochloride, COTI-2, miranserinb mesylate, MK-2206, MK-2206+ semantenib sulfate, ONC-201, PTX-200, TAS-117, trimetinib dimethyl sulfoxide+Uprivet, uprivet, ARQ-751, AT-13148, M2698, ALM-301, BAY-1125976, borussertib, DC-120, FXY-1, JRP-890, KS-99, NISC-6, RX-0201, or RX-0301, or a hydrate, solvate, or pharmaceutically acceptable salt thereof.

In some embodiments, the AKT inhibitor is administered at least once a week. In some embodiments, the AKT inhibitor is administered at least once daily. In some embodiments, the AKT inhibitor is administered once daily. In some embodiments, the AKT inhibitor is administered twice daily. In some embodiments, the AKT inhibitor is administered orally.

In some embodiments, the AKT inhibitor is administered at about 0.1mg to about 5000mg, e.g., about 1mg to about 3000mg, about 1mg to about 1000mg, about 1mg to about 500mg, about 1mg to about 100mg, about 10mg to about 2000mg, e.g., about 100mg to about 2000mg, about 100mg to about 1500mg, about 100mg to about 1000mg, about 100mg to about 800mg, about 100mg to about 600mg, about 100mg to about 400mg, about 100mg to about 200mg, about 200mg to about 2000mg, about 200mg to about 1500mg, about 200mg to about 1000mg, about 200mg to about 800mg, about 200mg to about 600mg, about 200mg to about 400mg, about 400mg to about 2000mg, about 400mg to about 1500mg, about 400mg to about 1000mg, about 400mg to about 800mg, about 600mg to about 600mg, about 600mg to about 1500mg, about 600mg to about 600mg, about 600mg to about 800 to about 600mg, about 800 to about 600mg, about 600mg to about 600mg, about 1500 mg. In some embodiments, the AKT inhibitor is administered at about 1mg per administration. In some embodiments, the AKT inhibitor is administered at about 5mg per administration. In some embodiments, the AKT inhibitor is administered at about 10mg per administration. In some embodiments, the AKT inhibitor is administered at about 50mg per administration. In some embodiments, the AKT inhibitor is administered at about 100mg per administration. In some embodiments, the AKT inhibitor is administered at about 200mg per administration. In some embodiments, the AKT inhibitor is administered at about 300mg per administration. In some embodiments, the AKT inhibitor is administered at about 400mg per administration. In some embodiments, the AKT inhibitor is administered at about 500mg per administration. In some embodiments, the AKT inhibitor is administered at about 600mg per administration. In some embodiments, the AKT inhibitor is administered at about 700mg per administration. In some embodiments, the AKT inhibitor is administered at about 800mg per administration. In some embodiments, the AKT inhibitor is administered at about 900mg per administration. In some embodiments, the AKT inhibitor is administered at about 1000mg per administration.

mTOR inhibitors

Examples of mTOR inhibitors include, but are not limited to: everolimus; zortress; sirolimus; temsirolimus; albumin-bound sirolimus; dactylisib tosylate; the onahasertib; DTRMWXHS-12+everolimus+pomalidomide (Zhejiang DTRM Biopharma LLC); bimiralisib; monetel; sapanantib (sapanisertib); paclitaxel + sirolimus + tamsulosin (Co-D Therapeutics Inc); sirolimus; vitacocrine (vistuertib); diutan (detosertib); ompaliib; prabetahistine mesylate (purinostat mesylate) d; NSC-765844 (National Cancer Institute US); OSU-53 (Ohio State University); OT-043 (Onco Therapies Inc); PQR-514 (PIQUR Therapeutics AG); QR-213 (Qrono Inc); SN-202 (Sichuan Sinovation Bio-technology Co Ltd); SPR-965 (Sphaera Pharma Pte Ltd); TAM-03 (Mount Tam Biotechnologies Inc); FP-208 (Beijing Foreland Pharma Co Ltd); HEC-68498 (HEC Pharm Co Ltd); LXI-15029 (Shandong Luoxin Pharmaceutical Group Stock Co Ltd); PTX-367 (Palvella Therapeutics LLC); WXFL-10030390 (Shanghai Jiatan Pharmaceutical Technology Co Ltd); XP-105 (Xynomic Pharmaceuticals Holdings Inc); AL-58805 (Advenchen Laboratories LLC); AL-58922 (Advenchen Laboratories LLC); AUM-302 (AUM Biosciences Pte Ltd); CA-102 (Curigin Co Ltd); CA-103 (Curigin Co Ltd); CT-365 (HEC Pharm Co Ltd); DFN-529 (Diffusion Pharmaceuticals Inc); DHM-25 (University of Rennes I);

RMC-5552 (Revolution Medicines Inc) having the structure:

CC-115 (Bristol-Myers Squibb Co) having the following structure:

ME-344 (MEIPhara Inc) having the following structure:

FT-1518 (FTG Bio LLC) having the structure:and

OSI-027 having the following structure:

and hydrates, solvates and pharmaceutically acceptable salts thereof.

In some embodiments, the mTOR inhibitor is everolimus, zortress, sirolimus, temsirolimus, albumin-bound sirolimus, dactolisib tosylate, onatasertib, DTRMWXHS-12+ everolimus+pomalidomide, bimiralisib, CC-115, monetel, sha Pase, sirolimus, valatide, diepastil, FP-208, HEC-68498, LXI-15029, ME-344, PTX-367, WXFL-10030390, XP-105, paclitaxel+sirolimus+tamsulosin, AL-58805, AL-58922, AUM-302, CA-102, CA-103, CT-365, DFN-529, DHM-25, FT-1518, NSC-765844, omipalisib, OSU-53, OT-043, R-514, prazistat mesylate, QR-213, RMC-5552, SN-202, SPR-965, TAM-03, or OSI-7, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable hydrate thereof. In some embodiments, the mTOR inhibitor is everolimus, or a pharmaceutically acceptable salt thereof.

In some embodiments, the mTOR inhibitor is administered at least once a week. In some embodiments, the mTOR inhibitor is administered at least once daily. In some embodiments, the mTOR inhibitor is administered once daily. In some embodiments, the mTOR inhibitor is administered twice daily. In some embodiments, the mTOR inhibitor is administered orally.

In some embodiments, the mTOR inhibitor is administered at about 0.1mg to about 5000mg, e.g., about 1mg to about 3000mg, about 1mg to about 1000mg, about 1mg to about 500mg, about 1mg to about 100mg, about 10mg to about 2000mg, e.g., about 100mg to about 2000mg, about 100mg to about 1500mg, about 100mg to about 1000mg, about 100mg to about 800mg, about 100mg to about 600mg, about 100mg to about 400mg, about 100mg to about 200mg, about 200mg to about 2000mg, about 200mg to about 1500mg, about 200mg to about 1000mg, about 200mg to about 800mg, about 200mg to about 600mg, about 200mg to about 400mg, about 400mg to about 2000mg, about 400mg to about 1500mg, about 400mg to about 1000mg, about 600mg to about 1500mg, about 600mg to about 1000mg, about 600mg to about 600mg, about 600mg to about 800 to about 600mg, about 1500mg to about 600mg, about 800 to about 600 mg. In some embodiments, the mTOR inhibitor is administered at about 1mg per administration. In some embodiments, the mTOR inhibitor is administered at about 5mg per administration. In some embodiments, the mTOR inhibitor is administered at about 10mg per administration. In some embodiments, the mTOR inhibitor is administered at about 50mg per administration. In some embodiments, the mTOR inhibitor is administered at about 100mg per administration. In some embodiments, the mTOR inhibitor is administered at about 200mg per administration. In some embodiments, the mTOR inhibitor is administered at about 300mg per administration. In some embodiments, the mTOR inhibitor is administered at about 400mg per administration. In some embodiments, the mTOR inhibitor is administered at about 500mg per administration. In some embodiments, the mTOR inhibitor is administered at about 600mg per administration. In some embodiments, the mTOR inhibitor is administered at about 700mg per administration. In some embodiments, the mTOR inhibitor is administered at about 800mg per administration. In some embodiments, the mTOR inhibitor is administered at about 900mg per administration. In some embodiments, the mTOR inhibitor is administered at about 1000mg per administration.

pan-HER inhibitors

Examples of pan-HER inhibitors include, but are not limited to:

ZW49 (zymewirks), PB 357 (Pfizer), MP 0274 (Molecular Partners), VRN 07 (Volronoi), saprotinib, zenocuzumab (zenocutuzumab), wave Ji Tini (poziotinib), mo Bo tinib (mobocertiinib), valitinib, pyrroltinib (pyrotinib), lapatinib, afatinib (afatinib), lenatinib or dacatinib, and

BDTX 189 with the following structure:

and hydrates, solvates and pharmaceutically acceptable salts thereof.

In some embodiments, the pan-HER inhibitor is ZW49, PB 357, MP 0274, VRN 07, BDTX 189, saprotinib, zetolizumab, wave Ji Tini, mo Bo tinib, valitinib, pyrroltinib, lapatinib, afatinib, lenatinib, or dacatinib, or a hydrate, solvate, or pharmaceutically acceptable salt thereof. In some embodiments, the pan-HER inhibitor is afatinib or a pharmaceutically acceptable salt thereof.

In some embodiments, the pan-HER inhibitor is administered at least once a week. In some embodiments, the pan-HER inhibitor is administered at least once daily. In some embodiments, the pan-HER inhibitor is administered once daily. In some embodiments, the pan-HER inhibitor is administered twice daily. In some embodiments, the pan-HER inhibitor is administered orally.

In some embodiments, the pan-HER inhibitor is administered at a dose of about 0.1mg to about 5000mg, e.g., about 1mg to about 3000mg, about 1mg to about 1000mg, about 1mg to about 500mg, about 1mg to about 100mg, about 10mg to about 2000mg, e.g., about 100mg to about 2000mg, about 100mg to about 1500mg, about 100mg to about 1000mg, about 100mg to about 800mg, about 100mg to about 600mg, about 100mg to about 400mg, about 100mg to about 200mg, about 200mg to about 2000mg, about 200mg to about 1500mg, about 200mg to about 1000mg, about 200mg to about 800mg, about 200mg to about 600mg, about 200mg to about 400mg, about 400mg to about 2000mg, about 400mg to about 1500mg, about 400mg to about 1000mg, about 400mg to about 800mg, about 400mg to about 600mg, about 600mg to about 2000mg, about 600mg to about 1500mg, about 600mg to about 1000mg, about 600mg to about 800mg, about 800mg to about 2000mg, about 800mg to about 1500mg, about 800mg to about 1000mg, about 600mg to about 2000mg, about 600mg to about 1500mg, about 600mg to about 1000mg, about 600mg to about 800 mg. In some embodiments, the pan-HER inhibitor is administered at about 1mg per administration. In some embodiments, the pan-HER inhibitor is administered at about 5mg per administration. In some embodiments, the pan-HER inhibitor is administered at about 10mg per administration. In some embodiments, the pan-HER inhibitor is administered at about 50mg per administration. In some embodiments, the pan-HER inhibitor is administered at about 100mg per administration. In some embodiments, the pan-HER inhibitor is administered at about 200mg per administration. In some embodiments, the pan-HER inhibitor is administered at about 300mg per administration. In some embodiments, the pan-HER inhibitor is administered at about 400mg per administration. In some embodiments, the pan-HER inhibitor is administered at about 500mg per administration. In some embodiments, the pan-HER inhibitor is administered at about 600mg per administration. In some embodiments, the pan-HER inhibitor is administered at about 700mg per administration. In some embodiments, the pan-HER inhibitor is administered at about 800mg per administration. In some embodiments, the pan-HER inhibitor is administered at about 900mg per administration. In some embodiments, the pan-HER inhibitor is administered at about 1000mg per administration.

EGFR inhibitors

Exemplary EGFR inhibitors include, but are not limited to:

ASK-120067 (Jiangsu Aosaikang Pharmaceutical Co Ltd) having the structure:

AST-2818 (Allist Shanghai Pharmaceutical Technology Co Ltd) having the following structure:

BI-4020 having the structure:

BDTX-189 (Black Diamond Therapeutics Inc) with the following structure:

BPI-7711 (Beta Pharma Inc) having the structure:

NRC-2694 (Natco Pharma Ltd) having the following structure:

SKLB-1028 (CSPC Pharmaceutical Group Ltd) having the structure:

TAS-6417 (Cullinan Oncology LLC) having the structure:

BAY-2476568 (Bayer) having the structure:

doxorubicin+erlotinib, rituximab+zatoxib, evighib maleate, ABP-1119 (AB Pharma Ltd), ABP-1130 (AB Pharma Ltd), afatinib, african afatinib, AG-101 (Arrogene Inc), AL-6802 (Jiangsu Simcere Pharmaceutical Co Ltd), ametinib mesylate, AM-105 (AbClon Inc), amelimumab, E Mo Tuo monoclonal antibody (amivanamab), AMX-3009 (Arromax Pharmatech Co Ltd), APL-1898 (Shangaai) Co Ltd), BBT-176 (Bridge Biotherapeutics Inc), BEBT-108 (Guangzhou BeBetter Medicine Technology Co Ltd), BEBT-109 (Guangzhou BeBetter Medicine Technology Co Ltd), BH-2922 (Beijing Hanmi Pharmaceutical Co Ltd), BLU-4810 (Blueprint Medicines Corp), BMX-002 (Biomunex Pharmaceuticals), BO-1978, BO-15086 (Betta Pharmaceuticals Co Ltd), buganinib (brinib), C-005 (C005), cexib (BIC-29), BIC-29 (BIB), C-95 (35), BIB-29 (35), C-95 (35), and Mawear-95 (BIP-35 (35), BIP-35 (BIP-35), CLwear-35 (BIP-29), CLwear-35 (BI), CLwear-95 (CLwear-35) Darafenib mesylate+panitumumab+trimetinib dimethyl sulfoxide, dacatinib, DBPR-112, rituximab (depatuzumab), DGD-1202 (MAIABiotechnology Inc), doxitinib mesylate, DZD-9008 (Dizal (Jiangsu) Pharmaceutical Co Ltd), EO-1001 (Senz Oncology Pty Ltd), ai Peiti, erlotinib (e.g. erlotinib hydrochloride), ES-072 (Apollomics Inc), FCN-411 (Fochon Pharma Inc), FHND-9041 (Jiangsu Zhengda Fenghai Pharmaceutical Co Ltd), FLAG-001 (Flag Therapeutics Inc), FLAG-003 (Flag Therapeutics Inc), fmAb-2 (Biocon Ltd), GB-263 (Genor BioPharma Co Ltd), GC-1118A (GC Pharma), gefitinib, GS-03+octtinib (Osimtinib), HA-12128 (CSPC Pharmaceutical Group Ltd), HMPL-309 (Hutchison MediPharma Ltd), HMPL-813 (Hutchison MediPharma Ltd), HS-Zhejiang Hisun Pharmaceutical Co Ltd), ecritinib hydrochloride, JMT-101 (JMP) and KN-411 (Fochon Pharma Inc), FHND-9041 (Jiangsu Zhengda Fenghai Pharmaceutical Co Ltd), FLAG-001 (Flag Therapeutics Inc), FLAG-003 (Flag Therapeutics Inc), FMAB-2 (Biocon Ltd), GB-263 (Genor BioPharma Co Ltd), GC-1118 (GC-03+Ksupport, ksupport device (XuanZhu Pharma Co Ltd), ksupport device (Ksupport device) and method for treating cancer with the drug delivery of the drug, lagranatinib (larotinib), lasatinib, liforafenib maleate, MCLA-129 (MeruNV), MCLA-158 (MeruNV), MDC-22 (Medicon Pharmaceuticals Inc), mo Bo tinib, mRX-7 (MiReven Pty Ltd), MTX-211 (Mekanistic Therapeutics LLC), MVC-101 (Maverick Therapeutics Inc), naquotinib mesylate, toxituzumab, lenatinib, nimotuzumab, NT-004 (NewGen Therapeutics Inc), NT-113 (NewGen Therapeutics Inc), OBX-1012 (Oncobix Co Ltd), otemtinib hydrochloride, octtinib (e.g., oxitinib mesylate), panitumumab, PB-4639, wave Ji Tini, pyrroltinib, QL-Qilu Pharmaceutical Co Ltd), QL-1203 (Qilu Pharmaceutical Co Ltd), RX-105 (ageranib, teva Pharmaceutical Industries Ltd), SAH-EJ1 (Arizona Cancer Therapeutics LLC), pratinib mesylate, TQ-200 (TQ-35), stratinib (TQ-48), stratinib (Shenzhen Targetrx Inc), TQ-48), ltimacyb (TQ-52 ) and TQ-48, TQvalatinib (TQ-52) and TQ-52-35 (TQb) are included UBP-1215 (Chi Cheung (Shanghai) Biomedical Co Ltd), vandetanib, varlitinib, VRN-071918 (Voronoi Group), VRN-6 (Voronoi Group), WBP-297 (Hualan Biological Engineering Inc), WJ-13404 (Wigen Biomedicine Technology (Shanghai) Co Ltd), WSD-0922 (Wayshine Biopharma Inc), XZP-5809 (Sihuan Pharmaceutical Holdings Group Ltd), inflitinib, YZJ-0318 (Yangtze River Pharmaceutical Group), ZNE-4 (Zentalis Pharmaceuticals Inc), zolitinib, ZR-2002 (McGill University) or ZSP-0391 (Guangdong Zhongsheng Pharmaceutical Co Ltd), JS-111 (Shanghai Junshi Biosciennce), LL-191 (Capella Therapeutics), ORIC-114 (Oric Pharmaceuticals), DS-2087b (Daiichi Sankyo), and hydrates, solvates and pharmaceutically acceptable salts thereof.

In some embodiments of the present invention, in some embodiments, EGFR inhibitors are doxorubicin+erlotinib, rituximab+zatoxib, eretinide maleate, ABP-1119, ABP-1130, afatinib dimaleate, AG-101, AL-6802, armetinib mesylate, AM-105, amelimumab, E Mo Tuoshan anti, AMX-3009, APL-1898, ASK-120067, AST-2818, BBT-176, BDTX-189, BEBT-108, BEBT-109, BH-2922, BLU-4810, BMX-002, BO-1978, BPI-15086, BPI-7711, bugatinib, C-005, cetuximab, CK-101, CLM-29, CLM-3, CMAB-017, CR-13626, CSHEGF-29, D-6, D2C 7-PVSRIPO 031 Darafenib mesylate+panitumumab+trimetinib dimethyl sulfoxide, dacatinib, DBPR-112, rituximab, DGD-1202, doxitinib mesylate, DZD-9008, EO-1001, ai Peiti, erlotinib (e.g. erlotinib hydrochloride), ES-072, FCN-411, FHND-9041, FLAG-001, FLAG-003, FAb-2, GB-263, GC-1118A, gefitinib, GS-03+Oritinib, HA-12128, HMPL-309, HMPL-813, HS-627, ecritinib hydrochloride, JRF-101, JRF-103, JZB-29, KBP-5209, KNP-501, KU-004, lapatinib (e.g. lapatinib ditoluenesulfonate), latinib, ratinib, lifanib maleate, MCLA-129, MCLA-158, MDC-22, mo Bo, mRX-7, MTX-211, MVC-101, naquotinib mesylate, nazatinib mesylate, cetuximab, lenatinib, nimotuzumab, NRC-2694, NT-004, NT-113, OBX-1012, omutinib hydrochloride, octtinib (e.g., octtinib mesylate), panitumumab, PB-357, bo Ji Tini, pyrroltinib, QL-1105, QL-1203, RXDX-105, SAH-EJ1, saprottinib, SCT-200 selatinib di-p-toluenesulfonate, cerotinib, SKLB-1028, SKLB-1206, SPH-118811, SYN-004, TAS-6417, tervaltinib p-toluenesulfonate, TGRX-360, tobrazib, TQB-3804, UBP-1215, vandetanib, varlitinib, VRN-071918, VRN-6, WBP-297, WJ-13404, WSD-0922, XZP-5809, inlitinib (yinlitinib), YZJ-0318, ZNE-4, zoribitinib, ZR-2002, ZSP-0391, ORIC-114, DS-2087b, JS-111, LL-191, BI-4020 or BAY-2476568, or a hydrate, solvate, or pharmaceutically acceptable salt thereof. In some embodiments, the EGFR inhibitor is afatinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the EGFR inhibitor is octreotide or a pharmaceutically acceptable salt thereof.

In some embodiments, the EGFR inhibitor is administered at least once a week. In some embodiments, the EGFR inhibitor is administered at least once daily. In some embodiments, the EGFR inhibitor is administered once daily. In some embodiments, the EGFR inhibitor is administered twice daily. In some embodiments, the EGFR inhibitor is administered orally.

In some embodiments, the EGFR inhibitor is administered at about 0.1mg to about 5000mg, e.g., about 1mg to about 3000mg, about 1mg to about 1000mg, about 1mg to about 500mg, about 1mg to about 100mg, about 10mg to about 2000mg, e.g., about 100mg to about 2000mg, about 100mg to about 1500mg, about 100mg to about 1000mg, about 100mg to about 800mg, about 100mg to about 600mg, about 100mg to about 400mg, about 100mg to about 200mg, about 200mg to about 2000mg, about 200mg to about 1500mg, about 200mg to about 1000mg, about 200mg to about 800mg, about 200mg to about 600mg, about 200mg to about 400mg, about 400mg to about 2000mg, about 400mg to about 1500mg, about 400mg to about 1000mg, about 600mg to about 1500mg, about 600mg to about 1000mg, about 600mg to about 600mg, about 1500mg to about 800 to about 600mg, about 800 to about 600 mg. In some embodiments, the EGFR inhibitor is administered at about 1mg per administration. In some embodiments, the EGFR inhibitor is administered at about 5mg per administration. In some embodiments, the EGFR inhibitor is administered at about 10mg per administration. In some embodiments, the EGFR inhibitor is administered at about 50mg per administration. In some embodiments, the EGFR inhibitor is administered at about 100mg per administration. In some embodiments, the EGFR inhibitor is administered at about 200mg per administration. In some embodiments, the EGFR inhibitor is administered at about 300mg per administration. In some embodiments, the EGFR inhibitor is administered at about 400mg per administration. In some embodiments, the EGFR inhibitor is administered at about 500mg per administration. In some embodiments, the EGFR inhibitor is administered at about 600mg per administration. In some embodiments, the EGFR inhibitor is administered at about 700mg per administration. In some embodiments, the EGFR inhibitor is administered at about 800mg per administration. In some embodiments, the EGFR inhibitor is administered at about 900mg per administration. In some embodiments, the EGFR inhibitor is administered at about 1000mg per administration.

MEK inhibitors

The MEK inhibitor may be a small molecule or biological inhibitor of the mitogen-activated protein kinase (MAPK) enzymes MEK1 and/or MEK2 (e.g., MAPK/ERK pathway).

Examples of MEK inhibitors include, but are not limited to:

trimetinib (also known as mekinest, GSK 1120212) having the following structure:

cobicitinib (cobimeinib) (also known as GDC-0973, xl 518) having the following structure:

bemetinib having the structure:

CI-1040 (also referred to as PD 184352) having the structure:

PD-325901 having the structure:

semantenib (also known as AZD 6244) having the following structure:

MEK162 having the structure:

AZD8330 having the structure:

TAK-733 having the structure:

GDC-0623 having the following structure:

rafacitinib (also known as RDEA119; BAY 869766) having the following structure:

pimasertib (also called AS 4987555) having the following structure:

RO 4987555 (also referred to as CH 4987555) having the following structure:

CInQ-03 having the following structure:

g-573 having the structure:

PD184161 having the following structure:

PD318088 having the following structure:

PD98059 having the following structure:

RO5068760 having the following structure:

SL327 having the following structure:

U0126 having the structure:

WX-554 (Wilex); and HL-085 (Shanghai Kechow Pharma), and pharmaceutically acceptable salts thereof.

In some embodiments, the MEK inhibitor is selected from: trametinib, cobicitinib, bemetinib, semetinib, PD-325901, CI-1040, MEK162, AZD8330, GDC-0623, refatinib, pimasertib, WX-554, HL-085, CH 4987555, TAK-733, CInQ-03, G-573, PD184161, PD318088, PD98059, RO5068760, U0126 and SL327, or pharmaceutically acceptable salts thereof.

In some embodiments, the MEK inhibitor is administered at least once a week (e.g., once a week, twice a week, three times a week, four times a week, five times a week, or six times a week). In some embodiments, the MEK inhibitor is administered once a week. In some embodiments, the MEK inhibitor is administered twice a week. In some embodiments, the MEK inhibitor is administered once daily. In some embodiments, the MEK inhibitor is administered twice daily. In some embodiments, the MEK inhibitor is administered for at least three weeks. In some embodiments, the MEK inhibitor is administered periodically (as a cycle) for three weeks, then discontinued for one week (three weeks after administration of the MEK inhibitor and then one week without administration of the MEK inhibitor). In some embodiments, the cycle is repeated at least once. In other embodiments, the MEK inhibitor is administered continuously (e.g., without discontinuation for one week).

In some embodiments, the MEK inhibitor is administered at about 0.1mg to about 100mg, e.g., about 0.1mg to about 50mg, about 0.1mg to about 10mg, about 0.1mg to about 5mg, about 0.1mg to about 4mg, about 0.1mg to about 3mg, about 0.1mg to about 2mg, about 0.1mg to about 1mg, about 1mg to about 10mg, about 1mg to about 20mg, about 1mg to about 40mg, about 1mg to about 60mg, about 1mg to about 80mg, about 1mg to about 100mg, about 10mg to about 100mg, about 20mg to about 100mg, about 40mg to about 100mg, about 60mg to about 100mg, or about 80mg to about 100mg per administration. In some embodiments, the MEK inhibitor is administered at about 0.5mg to about 10mg per administration. In some embodiments, the MEK inhibitor is administered at about 0.1mg, 0.2mg, 0.5mg, 1mg, 1.5mg, 3mg, 4mg, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, or 100mg per administration. In some embodiments, the MEK inhibitor is administered at about 4mg per administration. In some embodiments, the MEK inhibitor is administered at about 3.2mg per administration.

In some embodiments, the MEK inhibitor is administered orally.

In some embodiments, the MEK inhibitor is administered prior to the administration of the SHP2 inhibitor, SOS1 inhibitor, ERK1/2 inhibitor, CDK4/6 inhibitor, AKT inhibitor, mTOR inhibitor, pan-HER inhibitor, or EGFR inhibitor. In some embodiments, the MEK inhibitor is administered after the SHP2 inhibitor, SOS1 inhibitor, ERK1/2 inhibitor, CDK4/6 inhibitor, AKT inhibitor, mTOR inhibitor, pan-HER inhibitor, or EGFR inhibitor is administered. In some embodiments, the MEK inhibitor is administered concurrently with the SHP2 inhibitor, SOS1 inhibitor, ERK1/2 inhibitor, CDK4/6 inhibitor, AKT inhibitor, mTOR inhibitor, pan-HER inhibitor, or EGFR inhibitor.

Dual RAF/MEK inhibitors

In some embodiments, the dual RAF/MEK inhibitor is a compound of formula (I):

in some embodiments, the compound of formula (I) is:

which is also referred to herein as compound 1 or VS-6766 in free form.

In some embodiments, the dual RAF/MEK inhibitor is a pharmaceutically acceptable salt of a compound of formula (I). In some embodiments, the dual RAF/MEK inhibitor is a potassium salt of a compound of formula (I), also known as VS-6766. Other pharmaceutically acceptable salts of the compounds of formula (I) are contemplated herein.

The compounds of formula (I) and pharmaceutically acceptable salts thereof are dual RAF/MEK inhibitors that confer vertical inhibition of the MAPK pathway. In contrast to other MEK inhibitors, the compounds of formula (I) and pharmaceutically acceptable salts thereof are potent allosteric inhibitors of MEK kinase activity, which promote dominant negative RAF/MEK complexes, preventing the phosphorylation of MEK by wild-type RAF, V600E BRAF and CRAF. This mechanism allows compounds of formula (I) and pharmaceutically acceptable salts thereof to block MEK signaling without the occurrence of compensatory activation of MEK that appears to limit the efficacy of other inhibitors.

In some embodiments, the dual RAF/MEK inhibitor is a compound having the structure of formula (II):

Including pharmaceutically acceptable salts thereof, wherein:

ring A is

R ¹ 、R ² 、R ³ And R is ⁴ Each independently selected from: H. deuterium, hydroxy, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted ester, optionally substituted sulfonyl, optionally substituted S-sulfonamido, optionally substituted N-sulfonamido, optionally substituted sulfonate (sulfonate), optionally substituted O-thiocarbamoyl, optionally substituted N-carbamoyl, optionally substituted O-carbamoyl, optionally substituted urea, optionally substituted C1 to C6 alkoxy, optionally substituted C1 to C6 alkyl, optionally substituted C2 to C6 alkenyl, optionally substituted C2 to C6 alkynyl, optionally substituted C3 to C8 cycloalkyl, optionally substituted C6 to C10 aryl, optionally substituted C3 to C8 heterocyclyl, optionally substituted C3 to C10 heteroaryl, and L; r is R ⁶ Selected from: H. deuterium, hydroxy, halogen, cyano, nitro, optionally substituted amino, optionally substituted C1 to C6 alkoxy, optionally substituted C1 to C6 alkyl, optionally substituted C2 to C6 alkenyl and optionally substituted C2 to C6 alkynyl;

x is C (R) ⁵ ) ₂ ，CH(R ⁵ )，CH ₂ ，-O-，

L is-Z ₁ -Z ₂ or-Z ₁ -Z ₂ -Z ₃ ；

Z ₁ 、Z ₂ And Z ₃ Independently selected from: -CH ₂ -、-O-、-S-、S＝O、-SO ₂ -、C＝O、-CO ₂ -、-NO ₂ 、-NH-、-CH ₂ CCH、-CH ₂ CN、-NR ⁵ R ^5’ 、-NH(CO)-、-(CO)NH-、-(CO)NR ⁵ R ^5’ -、-NH-SO ₂ -、-SO ₂ -NH-、-R ⁵ CH _2- 、-R ⁵ O-、-R ⁵ S-、R ⁵ -S＝O、-R ⁵ SO _2- 、R ⁵ -C＝O、-R ⁵ CO _2- 、-R ⁵ NH-、-R ⁵ NH(CO)-、-R ⁵ (CO)NH-、-R ⁵ NH-SO _2- 、-R ⁵ SO ₂ -NH-、-NHCH ₂ CO-、-CH ₂ R ⁵ -、-OR ⁵ -、-SR ⁵ -、S＝O-R ⁵ 、-SO ₂ R ⁵ -、C＝O-R ⁵ 、-CO ₂ R ⁵ -、-NHR ⁵ -、-NH(CO)R ⁵ -、-(CO)NHR ⁵ -、-NH-SO ₂ R ⁵ -、-SO ₂ -NHR ⁵ -, optionally substituted C1 to C6 alkyl, optionally substituted C3 to C8 cycloalkyl, optionally substituted C6 to C10 aryl, optionally substituted C3 to C8 heterocyclyl, optionally substituted C3 to C10 heteroaryl, -CH ₂ - (optionally substituted aryl), -CH ₂ - (optionally substituted C3 to C8 cycloalkyl) and-CH ₂ - (optionally substituted C3 to C10 heteroaryl); each R ⁵ And R is ^5’ Independently selected from: H. deuterium, optionally substituted C1 to C6 alkyl, optionally substituted C2 to C6 alkenyl, optionally substituted C2 to C6 alkynyl, optionally substituted C3 to C8 carbocyclyl, optionally substituted C6 to C10 aryl, optionally substituted C3 to C8 heterocyclyl and optionally substituted C3 to C10 heteroaryl; and

y is CH ₂ NH or O, provided that R ¹ not-O-pyrimidinyl.

In some embodiments, the dual RAF/MEK inhibitor is a compound selected from the compounds in table I:

table I.

In some embodiments, the dual RAF/MEK inhibitor is IMM-1-104 (Immuneering) or a pharmaceutically acceptable salt thereof.

In some embodiments, the dual RAF/MEK inhibitor is administered at least once a week (e.g., once a week, twice a week, three times a week, four times a week, five times a week, or six times a week). In some embodiments, the dual RAF/MEK inhibitor is administered once a week. In some embodiments, the dual RAF/MEK inhibitor is administered twice a week. In some embodiments, the dual RAF/MEK inhibitor is administered once daily. In some embodiments, the dual RAF/MEK inhibitor is administered twice daily. In some embodiments, the dual RAF/MEK inhibitor is administered for at least three weeks. In some embodiments, the dual RAF/MEK inhibitor is administered periodically (as a cycle) for three weeks, then discontinued for one week (three weeks of dual RAF/MEK inhibitor administration, then one week of no dual RAF/MEK inhibitor administration). In some embodiments, the cycle is repeated at least once. In other embodiments, the dual RAF/MEK inhibitor is administered continuously (e.g., without discontinuation for one week).

In some embodiments, the dual RAF/MEK inhibitor is administered at about 0.1mg to about 100mg, e.g., about 0.1mg to about 50mg, about 0.1mg to about 10mg, about 0.1mg to about 5mg, about 0.1mg to about 4mg, about 0.1mg to about 3mg, about 0.1mg to about 2mg, about 0.1mg to about 1mg, about 1mg to about 10mg, about 1mg to about 20mg, about 1mg to about 40mg, about 1mg to about 60mg, about 1mg to about 80mg, about 1mg to about 100mg, about 10mg to about 100mg, about 20mg to about 100mg, about 40mg to about 100mg, about 60mg to about 100mg, or about 80mg to about 100mg per administration. In some embodiments, the dual RAF/MEK inhibitor is administered at about 0.5mg to about 10mg per administration. In some embodiments, the dual RAF/MEK inhibitor is administered at about 0.1mg, 0.2mg, 0.5mg, 1mg, 1.5mg, 3mg, 4mg, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, or 100mg per administration. In some embodiments, the dual RAF/MEK inhibitor is administered at about 4mg per administration. In some embodiments, the dual RAF/MEK inhibitor is administered at about 3.2mg per administration.

In some embodiments, dual RAF/MEK inhibitors (e.g., VS-6766) are administered at about 4mg twice weekly. In some embodiments, the dual RAF/MEK inhibitor (e.g., VS-6766) is administered at about 3.2mg twice weekly.

In some embodiments, the dual RAF/MEK inhibitor is administered orally.

In some embodiments, the dual RAF/MEK inhibitor is administered periodically for three weeks followed by a discontinuation of the administration for one week (three weeks of administration of the dual RAF/MEK inhibitor followed by one week of no administration of the dual RAF/MEK inhibitor). In some embodiments, the cycle is repeated at least once. In some embodiments, the cycle is repeated at least twice. In some embodiments, the cycle is repeated at least three times. In some embodiments, the dual RAF/MEK inhibitor is administered twice a week. In some embodiments, the dual RAF/MEK inhibitor is administered at about 0.5mg to about 10mg (e.g., about 4mg or about 3.2 mg) per administration. In some embodiments, the dual RAF/MEK inhibitor is administered at about 0.1mg to about 5mg per administration. In some embodiments, the dual RAF/MEK inhibitor is administered at about 1mg to about 5mg per administration. In some embodiments, the dual RAF/MEK inhibitor is administered at about 2mg to about 4mg per administration.

In some embodiments, the dual RAF/MEK inhibitor is administered in a twice-a-week cycle, wherein the cycle comprises administering the dual RAF/MEK inhibitor at a dose of about 0.5mg to about 10mg per administration for three weeks, followed by no administration of the dual RAF/MEK inhibitor for one week. In some embodiments, the dual RAF/MEK inhibitor is administered in a twice-a-week cycle, wherein the cycle comprises administering the dual RAF/MEK inhibitor at a dose of about 1mg to about 5mg per administration for three weeks, followed by no administration of the dual RAF/MEK inhibitor for one week. In some embodiments, the dual RAF/MEK inhibitor is administered in a twice-a-week cycle, wherein the cycle comprises administering the dual RAF/MEK inhibitor at a dose of about 2mg to about 4mg per administration for three weeks, followed by no administration of the dual RAF/MEK inhibitor for one week. In some embodiments, the dual RAF/MEK inhibitor is administered in a twice-a-week cycle, wherein the cycle comprises administering the dual RAF/MEK inhibitor at a dose of 3.2mg per administration for three weeks, followed by no administration of the dual RAF/MEK inhibitor for one week. In some embodiments, the dual RAF/MEK inhibitor is administered in a twice-a-week cycle, wherein the cycle comprises administering the dual RAF/MEK inhibitor at a dose of 4mg per administration for three weeks, followed by no administration of the dual RAF/MEK inhibitor for one week. In some embodiments, the cycle is repeated at least once.

In some embodiments, the dual RAF/MEK inhibitor is administered in a three-week cycle, wherein the cycle comprises administering the dual RAF/MEK inhibitor at a dose of about 0.8mg to about 10mg per administration for three weeks, followed by no administration of the dual RAF/MEK inhibitor for one week. In some embodiments, the dual RAF/MEK inhibitor is administered in a three-week cycle, wherein the cycle comprises administering the dual RAF/MEK inhibitor at a dose of about 1mg to about 5mg per administration for three weeks, followed by no administration of the dual RAF/MEK inhibitor for one week. In some embodiments, the dual RAF/MEK inhibitor is administered in a three-week cycle, wherein the cycle comprises administering the dual RAF/MEK inhibitor at a dose of about 2mg to about 4mg per administration for three weeks, followed by no administration of the dual RAF/MEK inhibitor for one week. In some embodiments, the dual RAF/MEK inhibitor is administered in a three-week cycle, wherein the cycle comprises administering the dual RAF/MEK inhibitor at a dose of 3.2mg per administration for three weeks, followed by no administration of the dual RAF/MEK inhibitor for one week. In some embodiments, the dual RAF/MEK inhibitor is administered in a three-week cycle, wherein the cycle comprises administering the dual RAF/MEK inhibitor at a dose of 4mg per administration for three weeks, followed by no administration of the dual RAF/MEK inhibitor for one week. In some embodiments, the cycle is repeated at least once.

In other embodiments, the dual RAF/MEK inhibitor is administered continuously (i.e., without a period of time (e.g., one week), wherein the dual RAF/MEK inhibitor is not administered). In some embodiments, the dual RAF/MEK inhibitor is administered once a week. In some embodiments, the dual RAF/MEK inhibitor is administered twice a week. In some embodiments, the dual RAF/MEK inhibitor is administered three times per week.

In some embodiments, the dual RAF/MEK inhibitor is administered prior to administration of the SHP2 inhibitor, SOS1 inhibitor, ERK1/2 inhibitor, CDK4/6 inhibitor, AKT inhibitor, mTOR inhibitor, pan-HER inhibitor, or EGFR inhibitor. In some embodiments, the dual RAF/MEK inhibitor is administered after administration of the SHP2 inhibitor, SOS1 inhibitor, ERK1/2 inhibitor, CDK4/6 inhibitor, AKT inhibitor, mTOR inhibitor, pan-HER inhibitor, or EGFR inhibitor. In some embodiments, the dual RAF/MEK inhibitor is administered concurrently with the SHP2 inhibitor, SOS1 inhibitor, ERK1/2 inhibitor, CDK4/6 inhibitor, AKT inhibitor, mTOR inhibitor, pan-HER inhibitor, or EGFR inhibitor.

Diseases and disorders

The methods provided herein are believed to be useful in the treatment of abnormal cell growth (e.g., cancer). For example, the cancer may include, but is not limited to, ovarian cancer, non-small cell lung cancer (e.g., NSCLC adenocarcinoma), endometrioid cancer, pancreatic adenocarcinoma, colorectal adenocarcinoma, or lung adenocarcinoma.

The methods provided herein are also expected to be useful for treating cancers identified as having a KRAS mutation, e.g., a KRAS G12X mutation (e.g., KRAS G12V, KRAS G12D, KRAS G12A, KRAS G12R, KRAS G12S, or KRAS G12C). In some embodiments, the cancer is characterized by having a KRAS mutation (e.g., a KRAS G12X mutation (e.g., KRAS G12V, KRAS G12D, KRAS G12A, KRAS G12R, KRAS G12S, or KRAS G12C)).

In some embodiments, the cancer is identified as having one or more KRAS mutations. In some embodiments, the KRAS mutation is a KRAS G12X mutation. In some embodiments, the KRAS mutation is a KRAS G12V mutation. In some embodiments, the KRAS mutation is a KRAS G12D mutation. In some embodiments, the KRAS mutation is a KRAS G12A mutation. In some embodiments, the KRAS mutation is a KRAS G12R mutation. In some embodiments, the KRAS mutation is a KRAS G12S mutation. In some embodiments, the KRAS mutation is a KRAS G12C mutation. In some embodiments, the KRAS mutation is a KRAS G13X mutation. In some embodiments, the KRAS mutation is a KRAS G13V mutation. In some embodiments, the KRAS mutation is a KRAS G13D mutation. In some embodiments, the KRAS mutation is a KRAS G13A mutation. In some embodiments, the KRAS mutation is a KRAS G13R mutation. In some embodiments, the KRAS mutation is a KRAS G13S mutation. In some embodiments, the KRAS mutation is a KRAS G13E mutation. In some embodiments, the KRAS mutation is a KRAS G12 dup mutation. In some embodiments, the KRAS mutation is a KRAS G13C mutation. In some embodiments, the KRAS mutation is a KRAS Q61X mutation. In some embodiments, the KRAS mutation is a KRAS Q61H mutation. In some embodiments, the KRAS mutation is a KRAS Q61K mutation. In some embodiments, the KRAS mutation is a KRAS Q61L mutation. In some embodiments, the KRAS mutation is a KRAS Q61R mutation. In some embodiments, the KRAS mutation is a KRAS Q61P mutation. In some embodiments, the KRAS mutation is a KRAS Q61E mutation.

The methods provided herein are also expected to be useful for treating cancers identified as having RAS pathway mutations (e.g., KRAS, NRAS, or HRAS).

In some embodiments, the cancer is identified as having a HRAS mutation.

In some embodiments, the cancer is identified as having NRAS mutation.

In some embodiments, the cancer is identified as having a RAF mutation.

In some embodiments, the cancer is identified as having a BRAF mutation. In some embodiments, the BRAF mutation is a BRAF V600 mutation. In some embodiments, the BRAF V600 is mutated to one or more BRAF V600E, BRAF V600K, BRAF V600D, BRAF V600R, or BRAF V600M mutations. In some embodiments, the BRAF V600 mutation is a BRAF V600E mutation. In some embodiments, the BRAF V600 mutation is a BRAF V600K mutation. In some embodiments, the BRAF V600 mutation is a BRAF V600D mutation. In some embodiments, the BRAF V600 mutation is a BRAF V600R mutation. In some embodiments, the BRAF V600 mutation is a BRAF V600M mutation.

In some embodiments, the cancer is identified as having an ARAF mutation.

In some embodiments, the cancer is identified as having a CRAF mutation.

In some embodiments, the cancer is identified as having a MEK1 and/or MEK2 mutation.

In some embodiments, the cancer is identified as having NF1 alterations, KRAS amplification, and/or NRAS amplification.

In some embodiments, the cancer is identified as having positive phosphorylated ERK protein expression (e.g., > 10%, > 20% or > 30% of cells) by immunohistochemical detection.

In some embodiments, the cancer is identified as having an EGFR change.

Abnormal cell growth

As used herein, abnormal cell growth refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition), unless otherwise indicated. This includes the following abnormal growths: (1) A proliferating tumor cell (tumor), for example, by expressing a mutated tyrosine kinase or overexpressing a receptor tyrosine kinase; (2) Benign and malignant cells of other proliferative diseases, for example, in which abnormal tyrosine kinase activation occurs; (3) Any tumor that proliferates through, for example, receptor tyrosine kinases; (4) For example any tumor that proliferates by aberrant serine/threonine kinase activation; and (5) benign and malignant cells of other proliferative diseases, such as serine/threonine kinase activation in which abnormalities occur. Abnormal cell growth may refer to the following cell growth: epithelial cells (e.g., carcinoma, adenocarcinoma); interstitial (e.g., sarcomas (e.g., leiomyosarcoma, ewing's sarcoma)); hematopoietic system (e.g., lymphoma, leukemia, myelodysplastic (e.g., premalignant)); or other (e.g., melanoma, mesothelioma, and other tumors of unknown origin).

Neoplastic disease

Abnormal cell growth may refer to neoplastic disease. A "neoplastic disease" is a disease or disorder characterized by cells having the ability to autonomously grow or replicate, for example, by an abnormal state or condition characterized by the growth of proliferative cells. Abnormal masses or "neo-organisms" of tissue due to abnormal cell growth or division may be benign, premalignant (carcinoma in situ) or malignant (cancer).

Exemplary neoplastic diseases include: carcinomas, sarcomas, metastatic diseases (e.g. tumors originating from the prostate, colon, lung, breast and liver), hematopoietic neoplastic diseases, e.g. leukemias, metastatic tumors. The amount of the compound treated is effective to ameliorate at least one symptom of the neoplastic disease, such as reduced cell proliferation, reduced tumor mass, and the like.

Cancer of the human body

The inventive methods of the present invention are useful for the prevention and treatment of cancers, including, for example, solid tumors, soft tissue tumors, and metastases thereof. The disclosed methods are also useful for treating non-solid cancers. Exemplary solid tumors include malignant tumors of different organ systems (e.g., sarcomas, adenocarcinomas, and carcinomas), such as those of the lung, breast, lymph, gastrointestinal tract (e.g., colon), and genitourinary tract (e.g., kidney, urothelium, or testicular tumor), pharynx, prostate, and ovary. Exemplary adenocarcinomas include colorectal cancer, renal cell carcinoma, liver cancer (e.g., hepatocellular carcinoma), non-small cell carcinoma of the lung, pancreatic cancer (e.g., metastatic pancreatic cancer), and small intestine cancer.

The cancer may include Esophageal Squamous Cell Carcinoma (ESCC); gastrointestinal stromal tumor (GIST); head and neck cancer, squamous cell carcinoma, bladder cancer; colorectal cancer; pancreatic ductal carcinoma; triple Negative Breast Cancer (TNBC), mesothelioma; neurofibromatosis; for example, type 2 neurofibromatosis, type 1 neurofibromatosis; renal cancer; lung cancer, non-small cell lung cancer; liver cancer; thyroid cancer; ovarian cancer; breast cancer; tumors of the nervous system; a schwannoma; meningioma; schwannoma disease; auditory neuroma; adenoid cystic carcinoma; ventricular tube membranoma; a ependymal tumor, or any other tumor exhibiting reduced merlin expression and/or mutation, and/or NF-2 gene deletion and/or promoter hypermethylation. In some embodiments, the cancer is renal cancer.

Cancers may include cancers characterized by comprising cancer stem cells, cancer-associated mesenchymal cells, or tumor-initiating cancer cells. Cancers may include cancers that have been characterized as enriched for cancer stem cells, cancer-associated mesenchymal cells, or tumor-forming cancer cells (e.g., tumors or metastatic tumors enriched for cells undergoing epithelial-to-mesenchymal transformation).

The cancer may be a primary tumor, i.e. an anatomical site located at the beginning of tumor growth. The cancer may also be metastatic, i.e. at least a second anatomical site is present in addition to the anatomical site where tumor growth begins. The cancer may be a recurrent cancer, i.e., a cancer that recurs after treatment and after a period of time in which the cancer is undetectable. Recurrent cancer may be anatomically located near the primary tumor, e.g., anatomically close to the primary tumor; in the area of the primary tumor, for example in the lymph nodes near the primary tumor; or away from the primary tumor, e.g., anatomically away from the area of the primary tumor.

Cancers may also include, for example, but are not limited to, epithelioid cancer, breast cancer, lung cancer, pancreatic cancer, colorectal cancer (e.g., metastatic colorectal cancer, e.g., metastatic KRAS mutant), prostate cancer, head and neck cancer, melanoma (e.g., locally advanced or metastatic malignant cutaneous melanoma with NRAS mutations), acute myelogenous leukemia, and glioblastoma. Exemplary breast cancers include triple negative breast cancer, basal-like breast cancer, claudin-low breast cancer, invasive, inflammatory, metaplastic and advanced HER-2 positive or ER-positive cancers, which are resistant to treatment.

The cancer may also include cancers with SHP2 mutations, SOS1 mutations, ERK1/2 mutations, CDK 4/6 mutations, AKT mutations, mTOR mutations, pan-HER mutations, or EGFR alterations.

The cancer may also include lung adenocarcinoma, colorectal carcinoma, uveal melanoma, ovarian carcinoma, endometrioid carcinoma, bladder urothelial carcinoma, breast invasive lobular carcinoma, cervical squamous cell carcinoma, cutaneous melanoma, cervical adenocarcinoma, hepatocellular carcinoma, pancreatic carcinoma, bipolar pleural mesothelioma, renal clear cell carcinoma, gastric adenocarcinoma, tubular gastric adenocarcinoma, uterine carcinomatosis, or uterine malignant mixed Mullerian tumor.

Other cancers include, but are not limited to, uveal melanoma, brain cancer, abdominal cancer, esophageal cancer, gastrointestinal cancer, glioma, liver cancer, tongue cancer, neuroblastoma, osteosarcoma, ovarian cancer, retinoblastoma, nephroblastoma, multiple myeloma, skin cancer, lymphoma, hematological cancer, and bone marrow cancer (e.g., advanced hematological malignancy, leukemia, such as acute myelogenous leukemia (e.g., primary or secondary), acute lymphoblastic leukemia, T-cell leukemia, hematological malignancy, advanced myeloproliferative disease, myelodysplastic syndrome, recurrent or refractory multiple myeloma, advanced myeloproliferative disease), retinal cancer, bladder cancer, cervical cancer, renal cancer, endometrial cancer, meningioma, lymphoma, skin cancer, uterine cancer, lung cancer, non-small cell lung cancer, nasopharyngeal carcinoma, neuroblastoma, solid tumors, hematological malignancy, cancer, squamous cell carcinoma, brain cancer, vulval carcinoma, vulval sarcoma, intestinal cancer, oral cavity cancer, endocrine carcinoma, seminal carcinoma, testicular cancer, diffuse cancer of the thyroid gland, diffuse cell, diffuse cancer, malignant tumor, and malignant tumor-associated cancer of the thyroid gland, and malignant tumor-like, carcinoma.

In some embodiments, the tumor is a solid tumor. In some embodiments, the solid tumor is locally advanced or metastatic. In some embodiments, the solid tumor is refractory (e.g., resistant) to standard post-treatment.

In some embodiments, the cancer is lung cancer (e.g., non-small cell lung cancer (NSCLC), e.g., KRAS mutated NSCLC; metastatic cancer), bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer (e.g., unresectable lower ovarian cancer, advanced or metastatic ovarian cancer), rectal cancer, cancer of the anal region, gastric cancer, colon cancer, breast cancer (e.g., triple negative breast cancer (e.g., breast cancer that does not express the genes of estrogen receptor, progesterone receptor, and Her 2/neu)), uterine cancer, fallopian tube cancer, endometrioid cancer, cervical cancer, vaginal cancer, vulval cancer, hodgkin's disease, cancer of the esophagus (esophageal cancer), small intestine cancer, cancer of the endocrine system, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, renal cancer or ureteral cancer, renal cell carcinoma, renal pelvis cancer, tumors of the Central Nervous System (CNS), primary CNS lymphoma, spinal column tumor, brain stem glioma, pituitary adenoma, mesothelioma (e.g., malignant mesothelioma, such as may be resected by surgery), or a combination of one or more of the above). In some embodiments, the cancer is metastatic. In some embodiments, the abnormal cell growth is locally recurrent (e.g., the subject has a locally recurrent disease, e.g., cancer).

The methods described herein may reduce, ameliorate, or completely eliminate the disorder and/or its associated symptoms, to prevent its deterioration, to slow the rate of progression, or to minimize its recurrence rate (i.e., avoid recurrence) after the disorder is initially eliminated. The appropriate dosage and treatment regimen may vary depending upon the particular compound, combination and/or pharmaceutical composition employed and the mode of delivery of the compound, combination and/or pharmaceutical composition. In some embodiments, the methods increase the average survival, increase the average length of progression-free survival, and/or decrease the rate of recurrence of a subject treated with a combination described herein in a statistically significant manner.

Other therapies

In some embodiments, the methods and compositions described herein are administered with additional therapies (e.g., cancer treatment). In one embodiment, a mixture or pharmaceutical composition of one or more compounds may be administered to a subject in need thereof, along with a combination as described herein. In yet another embodiment, one or more compounds or compositions (e.g., pharmaceutical compositions) may be administered with a combination as described herein for the treatment or prevention of various diseases, including, for example, cancer, diabetes, neurodegenerative diseases, cardiovascular disease, coagulation, inflammation, flushing, obesity, aging, stress, and the like. In various embodiments, combination therapies comprising a compound or pharmaceutical composition described herein may refer to (1) pharmaceutical compositions comprising one or more compounds in combination with a combination described herein; and (2) co-administering one or more compounds or pharmaceutical compositions described herein with a combination described herein, wherein the compounds or pharmaceutical compositions described herein are not yet formulated in the same composition. In some embodiments, the combinations described herein are administered with additional treatments (e.g., additional cancer treatments). In some embodiments, the additional treatment (e.g., additional cancer treatment) may be administered simultaneously (e.g., at the same time), in the same or separate compositions, or sequentially. Sequential administration refers to administration of one treatment immediately prior to (e.g., less than 5, 10, 15, 30, 45, 60 minutes; 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 48, 72, 96 or more hours; 4, 5, 6, 7, 8, 9 or more days; 1, 2, 3, 4, 5, 6, 7, 8 or more weeks prior to administration of another, e.g., second treatment (e.g., compound or therapy). The order of administration of the first and second compounds or therapies may also be reversed.

Exemplary cancer treatments include, for example: chemotherapy, targeted therapies such as antibody therapy, immunotherapy and hormone therapy. Examples of each of these treatments are provided below.

Chemotherapy treatment

In some embodiments, the combination described herein is administered with chemotherapy. Chemotherapy is the treatment of cancer with drugs that can destroy cancer cells. "chemotherapy" generally refers to cytotoxic drugs that, in contrast to targeted therapies, generally affect rapidly dividing cells. Chemotherapeutic agents interfere with cell division in a variety of possible ways, e.g., replication of DNA or isolation of newly formed chromosomes. While a degree of specificity may be produced by many cancer cells failing to repair DNA damage, most normal cells are typically able to repair, most forms of chemotherapy target all rapidly dividing cells and are not specific to cancer cells.

Examples of chemotherapeutic agents for cancer treatment include, for example, antimetabolites (e.g., folic acid, purine and pyrimidine derivatives) and alkylating agents (e.g., nitrogen mustards, nitrosoureas, platinum, alkyl sulfonates, hydrazines, triazenes, aziridines, spindle toxins, cytotoxic agents, topoisomerase inhibitors, and the like). Exemplary agents include aclarubicin, actinomycin, alithetin, altreton, altretamine, aminopterin, aminolevulinic acid, amrubicin, amsacrine, anagrelide, arsenic trioxide, asparaginase, atrasentan, belothiocan, bexarotene, endamstine, bleomycin, bortezomib, busulfan, camptothecine, capecitabine, carboplatin, carboquinone, carmofur, carmustine, celecoxib chlorambucil, nitrogen mustard, cisplatin, cladribine, clofarabine, crisantaaspase, cyclophosphamide, cytarabine, dacarbazine, actinomycin D, daunorubicin, decitabine, dimecoxin docetaxel, doxorubicin, etoposide (Efaproxiral), i Li Simo, elsamitrucin, enocitabine, epirubicin, estramustine, etoposide, floxuridine, fludarabine, fluorouracil (5 FU), fotemustine, gemcitabine, gliadel implants, hydroxyurea (hydroxyarbamide), hydroxyurea (Hydroxyurea), idarubicin, ifosfamide, irinotecan, ilofirofen, ixabepilone, raloxine, calcium folinate, doxorubicin liposomes, daunorubicin liposomes, lonimine, lomustine, thioanthrone, mannsuloshu, masorol, melphalan, mercaptopurine, mesna, methotrexate, minovalerate, dibromomannitol, mitoguazone, mitotane, mitomycin, mitoxantrone, nedaplatin, nimustine, olympicin, oxabane, pennistin, piramide, pirarubicin, agamycin, pramipenem, sodium, phenomycin, procalcitonin, procarbazine, and the like, rapamycin, lubitecan, sapatacitabine, semustine, celecoxib Ma Ji (sitimagene ceradenovec), satraplatin (straaplatin), streptozotocin, talaporfin, tegafur-uracil, temoporfin, temozolomide, teniposide, temozolomide, testosterone, tetranitate (tetranitate), thiotepa, thiflulin, thioguanine, tepirfenib, topotecan, trabectedin, triamcinolone, tritlatin, retinoic acid, troxiv, triamcinolone, urapidine, valrubicin, verteporfin, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, lithostat, zorubicin, and other cytostatics or cytotoxic agents described herein.

Because certain drugs are used in combination more effectively than alone, two or more drugs are often used simultaneously or sequentially. Typically, two or more chemotherapeutic agents are used as a combination chemotherapy. In some embodiments, the chemotherapeutic agent (including combination chemotherapy) may be used in combination with a combination as described herein.

Targeted therapy

In some embodiments, the combinations described herein are administered with targeted therapies. Targeted therapies consist of agents that use deregulated proteins specific for cancer cells. Small molecule targeted therapy drugs are typically inhibitors of the enzymatic domain on mutations, overexpression or other critical proteins within cancer cells. Prominent examples are tyrosine kinase inhibitors such as Axitinib (axiinib), bosutinib (Bosutinib), ceridinib (Cediranib), dasatinib (desatinib), erlotinib (erlotinib), imatinib, gefitinib, lapatinib, letatinib (lebamutinib), nilotinib (Nilotinib), semaxanib (Semaxanib), sorafenib, sunitinib and Vandetanib (vanretanib), and cyclin-dependent kinase inhibitors such as Alvocidib and Seliciclib. Monoclonal antibody therapy is another strategy in which the therapeutic agent is an antibody that specifically binds to a protein on the surface of cancer cells. Examples include the anti-HER 2/neu antibody trastuzumab commonly used for breast cancer And rituximab and tositumomab, anti-CD 20 antibodies commonly used in a variety of B cell malignancies. Other exemplary antibodies include, but are not limited to, cetuximab, panitumumab, trastuzumab, alemtuzumab, bevacizumab, edestin and gemtuzumab. Exemplary fusion proteins include, abelmoschus (Aflibeccept) and diniinterleukin (Denileukin diftitox)). In some embodiments, targeted therapies may be used in combination with the combinations described herein.

Targeted therapies may also involve small peptides as "homing devices" which can bind cell surface receptors or affect the extracellular matrix surrounding the tumor. Radionuclides attached to these peptides (e.g., RGD) eventually kill cancer cells if the nuclides decay in the vicinity of the cells. One example of such a therapy includes

Immunotherapy

In some embodiments, the combination described herein is administered with an immunotherapy. Cancer immunotherapy refers to a variety of therapeutic strategies aimed at inducing the patient's autoimmune system against tumors.

Modern methods of generating immune responses against tumors include intracapsular BCG immunotherapy against superficial bladder cancer, and induction of immune responses in subjects with renal cell carcinoma and melanoma using interferons and other cytokines. Allogeneic hematopoietic stem cell transplantation can be considered an immunotherapy, as donor immune cells will often trigger tumors with graft-versus-tumor effects. In some embodiments, immunotherapeutic agents may be used in combination with the combinations described herein.

Hormone therapy

In some embodiments, the described combination is administered with hormonal therapy. The growth of certain cancers may be inhibited by providing or blocking certain hormones. Common examples of hormone sensitive tumors include certain types of breast and prostate cancers. Removal or blocking of estrogen or testosterone is often an important additional treatment. In certain cancers, administration of a hormonal agonist, such as a progestin, may be beneficial for treatment. In some embodiments, hormonal therapeutic agents may be used in combination with the combinations described herein.

Radiation therapy

The combinations described herein can be used in combination with directed energy or particles, or with radioisotope therapy (e.g., radiation therapy, e.g., radiooncology) to treat proliferative diseases, such as cancer, e.g., cancer associated with cancer stem cells. The combinations described herein may be administered to a subject simultaneously or sequentially with targeted energy or particle or radioisotope therapy. For example, the combinations described herein may be administered prior to, during, or after targeted energy or particles, or radioisotope therapy, or a combination thereof. Directed energy or particle therapy may include whole body irradiation, localized body irradiation, or spot irradiation. The directed energy or particles may originate from an accelerator, synchrotron, nuclear reaction, vacuum tube, laser or radioisotope. The therapy may include external-ray radiation therapy, teletherapy, brachytherapy, sealed source radiation therapy, systemic radioisotope therapy or unsealed source radiation therapy. Treatment may include ingestion of a radioisotope (e.g., radioiodine, cobalt, cesium, potassium, bromine, fluorine, carbon), or placement in proximity to the radioisotope. External-ray radiation therapy may include exposure to directed alpha particles, electrons (e.g., beta particles), protons, neutrons, positrons, or photons (e.g., radio waves, millimeter waves, microwaves, infrared, visible light, ultraviolet, X-rays, or gamma rays). The radiation may be directed to any portion of the subject in need of treatment.

Surgery

The combinations described herein can be used in combination with surgery (e.g., surgical exploration, intervention, biopsy) to treat proliferative disorders, such as cancer, e.g., cancer associated with cancer stem cells. The combinations described herein may be administered to a subject concurrently with surgery or sequentially. For example, the combinations described herein may be administered prior to surgery (preoperative), during surgery or after surgery (post-operative), or a combination thereof. The procedure may be a biopsy, in which one or more cells are collected for further analysis. The biopsy may be done, for example, with a scalpel, needle, catheter, endoscope, spatula or scissors. The biopsy may be a resected biopsy, an incision biopsy, a center biopsy or a needle biopsy, such as a needle biopsy. Surgery may involve removing local tissue suspected or identified as cancerous. For example, the process may involve removal of cancerous lesions, bumps, polyps, or moles. This operation may involve removing a large amount of tissue, such as breast, bone, skin, fat, or muscle. The procedure may involve removing a portion or all of an organ or nodule, such as a lung, throat, tongue, bladder, cervix, ovary, testis, lymph node, liver, pancreas, brain, eye, kidney, gall bladder, stomach, colon, rectum or intestine. In one embodiment, the cancer is breast cancer, e.g., triple negative breast cancer, and the surgery is mastectomy or lumpectomy.

Anti-inflammatory agent

The combinations described herein may be administered with an anti-inflammatory agent. Anti-inflammatory agents may include, but are not limited to, non-steroidal anti-inflammatory agents (e.g., salicylates (aspirin, acetylsalicylic acid), diflunisal, bissalicylates), propionic acid derivatives (ibuprofen, naproxen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin, loxoprofen), acetic acid derivatives (indomethacin, sulindac, etodolac, ketorolac, diclofenac, nabumetone), enolic acid (oxicam) derivatives (piroxicam, meloxicam, tenoxicam, droxic, lornoxicam, isoxicam), fenamic acid derivatives (fenamic acid esters) (mefenamic acid, meclofenamic acid, flufenamic acid), tolfenamic acid), selective COX-2 inhibitors (Coxibs) (celecoxib), sulfonanilides (nimesulide), steroids (e.g., hydrocortisone), cortisone acetate, prednisone, prednisolone, methylprednisolone, dexamethasone, triamcinolone acetate, betamethasone acetate, and the like.

Analgesic agent

Analgesics include, but are not limited to, opioids (e.g., morphine, codeine, oxycodone, hydrocodone, dihydromorphine, dolantine, buprenorphine, tramadol, venlafaxine), paracetamol and non-steroidal anti-inflammatory agents (e.g., salicylates (aspirin (acetylsalicylic acid), diflunisal, bissalicylate), propionic acid derivatives (ibuprofen, naproxen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin, loxoprofen), acetic acid derivatives (indomethacin, sulindac, etodolac, ketorolac, diclofenac, nabumetone), enolic acid (oxicam) derivatives (piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, isoxicam), fenamic acid derivatives (fenamic acid esters) (mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid), selective COX-2 inhibitors (coxib) (celecoxib), sulfenamide (sulindac).

Antiemetic medicine

The combinations described herein may be administered with an antiemetic. Antiemetics may include, but are not limited to, 5-HT3 receptor antagonists (dolasetron (Anzemet), granalon (Kytril, sancuso), ondansetron (Zofran), tropisetron (Navoban), palonosetron (Aloxi), mirtazapine (Remeron), dopamine antagonists (domperidone, olanzapine, haloperidol, chlorpromazine, promethazine, prochlorperazine, methoprene (Reglan), aripride, prochlorperazine (Compazine, stemzine, buccastem, stemetil, phenotil), NK1 receptor antagonists (aprepand), anti-resistive amine drugs (cyprohexazine, benalamine, theabehenamine (Gravol), meclozine (Bonine, antivertet), promethazine, oxazine, benzodiazine, benzodiazepine, and desipram).

Combination of two or more kinds of materials

The phrase "combination" and the term "co-administer," "co-administer," or "co-provide," as used herein in the context of administering a compound described herein or a therapy described herein, refers to delivering two (or more) different compounds or therapies to a subject during a subject suffering from a disease or disorder (e.g., a disease or disorder described herein, such as cancer), e.g., after a subject is diagnosed with a disease or disorder (e.g., a disease or disorder described herein, such as cancer) and before the disease or disorder is cured or eliminated or otherwise stopped.

In some embodiments, delivery of one compound or therapy is still in progress at the beginning of the second delivery, such that there is overlap in administration. This is sometimes referred to herein as "simultaneous" or "simultaneous delivery. In other embodiments, the delivery of one compound or therapy is ended before the delivery of the other compound or therapy begins. In some embodiments in either case, the treatment (e.g., administration of a compound, composition, or treatment) is more effective due to the combined administration. For example, a second compound or therapy is more effective, e.g., an equivalent effect can be seen with less of the second compound or therapy than seen with administration of the second compound or therapy in the absence of the first compound or therapy, or the second compound or therapy reduces symptoms to a greater extent, or similar conditions can be seen with the first compound or therapy. In some embodiments, the delivery results in a greater reduction in symptoms or other parameters associated with the disorder than would be observed in the absence of one compound or therapy delivered with the other compound or therapy. The effects of the two compounds or therapies may be partially additive, fully additive, or greater than additive (e.g., synergistic). When the second is delivered, the delivery may be such that the effect of the delivered first compound or therapy is still detectable.

In some embodiments, the first compound or therapy and the second compound or therapy may be administered simultaneously (e.g., at the same time), in the same or separate compositions, or sequentially. Sequential administration refers to administration of one compound or therapy immediately prior to administration of another, e.g., less than 5, 10, 15, 30, 45, 60 minutes; 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 48, 72, 96 or more hours; 4, 5, 6, 7, 8, 9 or more days; 1, 2, 3, 4, 5, 6, 7, 8 or more weeks. The order of administration of the first and second compounds or therapies may also be reversed.

The combination described herein may be a first line treatment of abnormal cell growth (e.g., cancer), i.e., for a patient who has not previously been administered another drug intended to treat cancer; a second line treatment of cancer, i.e., it is for a subject in need thereof who has been previously administered another drug intended to treat cancer; the third or fourth treatment of cancer, i.e., it is for a subject who has previously been administered two or three other drugs intended to treat cancer.

In some embodiments, the combinations described herein provide a synergistic effect. Synergy scores can be calculated using 4 different methods (Bliss, loewe, HSA and ZIP) in combination.

In some embodiments, the SHP2 inhibitor, SOS1 inhibitor, ERK1/2 inhibitor, CDK4/6 inhibitor, AKT inhibitor, mTOR inhibitor, pan-HER inhibitor, or EGFR inhibitor and MEK inhibitor are administered in amounts (e.g., dosages) that produce a synergistic (e.g., therapeutic) effect.

In some embodiments, the SHP2 inhibitor, SOS1 inhibitor, ERK1/2 inhibitor, CDK4/6 inhibitor, AKT inhibitor, mTOR inhibitor, pan-HER inhibitor, or EGFR inhibitor and dual RAF/MEK inhibitor are administered in amounts (e.g., dosages) that produce a synergistic (e.g., therapeutic) effect.

Administration and dosage

The combination of the invention may be administered orally, parenterally, topically, rectally or by an implantable kit (implanted reservoir), preferably by oral administration or by injection. In some cases, the pH of a composition (e.g., a pharmaceutical composition) may be adjusted with a pharmaceutically acceptable acid, base, or buffer to enhance the stability or efficacy of the composition.

In some embodiments, the subject orally administers the composition (e.g., a pharmaceutical composition). In some embodiments, the composition (e.g., pharmaceutical composition) is administered orally in any orally acceptable dosage form, including, but not limited to, liquid-gel tablets or capsules, syrups, emulsions, and aqueous suspensions. The liquid-gel may contain gelatin, plasticizers and/or opacifiers as desired to achieve a suitable consistency, and may be coated with an approved-for-use enteric coating, such as shellac. When used as an oral dosage, additional thickening agents, for example, gums such as xanthan gum, starches such as corn starch or gluten, may be added to achieve the desired consistency of the composition (e.g., pharmaceutical composition). Some sweetener and/or flavoring and/or coloring agents may be added if desired.

In some embodiments, the composition (e.g., pharmaceutical composition) is administered to the subject in a form suitable for oral administration, such as tablets, capsules, pills, powders, sustained release formulations, solutions, and suspensions. The composition (e.g., pharmaceutical composition) may be in unit dosage form suitable for single administration in precise doses. In addition to the compounds described herein, the pharmaceutical compositions may also comprise a pharmaceutically acceptable carrier, and may optionally further comprise one or more pharmaceutically acceptable excipients, for example, stabilizers, diluents, binders, and lubricants. In addition, the tablets may contain other drugs or agents, carriers and/or adjuvants. Exemplary pharmaceutical compositions include compressed tablets (e.g., directly compressed tablets).

Tablets containing the active ingredient or therapeutic ingredient (e.g., a compound described herein) are also provided. In addition to the active or therapeutic ingredient, the tablet may also contain a large amount of inert material, such as a carrier. Pharmaceutically acceptable carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, sesame oil and the like. Saline solutions and aqueous dextrose may also be employed as liquid carriers. Thus, the oral dosage forms used according to the invention may be formulated in conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active ingredients into preparations which can be used pharmaceutically. Excipients can provide a pressed material with good powder flow and compaction characteristics. Examples of excipients are described, for example, in Handbook of Pharmaceutical Excipients (5 th edition) edited by Raymond C Rowe, paul j. Sheskey, and Sian C. Owen; the publisher: pharmaceutical publishers.

For oral administration, the active ingredient (e.g., a compound described herein) can be readily formulated by combining the active ingredient with pharmaceutically acceptable carriers well known in the art. These carriers are capable of formulating the active ingredients of the present invention into tablets, pills, capsules, liquids, gels, syrups, slurries, powders or granules, suspensions or solutions in water or non-aqueous medium, and the like, for oral ingestion by a subject. Solid excipients can be used to prepare pharmaceutical formulations for oral use, the resulting mixture is optionally ground, and the mixture of granules is processed after adding suitable adjuvants (if desired) to obtain, for example, tablets. Suitable excipients such as diluents, binders or disintegrants may be required.

The dosage may vary depending upon the dosage form employed and the route of administration employed. The exact dosage form, route of administration and dosage may be selected by the respective physician according to the condition of the patient (see, e.g., fingl et al, 1975, "The Pharmacological Basis of Therapeutics"). Lower or higher doses than those listed above may be required. The specific dosage and treatment regimen of any particular subject will depend upon a variety of factors including the activity of the particular compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, disorder or condition, the subject's disposition to the disease, disorder or condition, and the discretion of the attendant physician. The course of treatment may include one or more separate administrations of the compounds of the present invention. The course of treatment may include one or more cycles of a compound described herein.

In some embodiments, a cycle as used herein in the context of a drug administration cycle refers to a period of time during which a drug is administered to a patient. For example, if the drug is administered at a period of 21 days, the periodic administration is, for example, administered once daily or twice daily for 21 days. A drug may be administered for more than one period. The rest period may be between two cycles. The rest period may be 1, 2, 4, 6, 8, 10, 12, 16, 20, 24 hours, 1, 2, 3, 4, 5, 6, 7 days or 1, 2, 3, 4 weeks or longer.

If desired, the oral dosage form may be presented in a packaging or dispenser device, such as an FDA approved kit, which may contain one or more unit dosage forms containing the active ingredient. The package may for example comprise a metal or plastic foil, such as a blister package. The package or dispenser device may be accompanied by instructions for administration. The package or dispenser device may also be accompanied by a notice in the form prescribed by a government agency related to the container that prescribes manufacture, use or sale of pharmaceuticals, the notice reflecting approval by the agency of the form of administration of the composition or human or veterinary. For example, such notification may be a label for prescription drugs approved by the U.S. food and drug administration or an approved product insert.

Screening

The methods provided herein also include methods for screening or identifying subjects having cancers suitable for treatment with a MEK inhibitor or dual RAF/MEK inhibitor in combination with an SHP2 inhibitor. For example, the methods are directed to identifying a subject who is likely to respond to the cancer treatments described herein. Also provided are methods for optimizing the efficacy of treatment of a subject having cancer, wherein the treatment comprises administration of a MEK inhibitor or a combination of a dual RAF/MEK inhibitor and an SHP2 inhibitor.

In one aspect, provided herein is a method of detecting the presence of a SHP2 gene mutation associated with a subject having cancer, the method comprising:

(a) Obtaining a biological sample from a subject; and

(b) Detection is performed and the samples are screened for mutations.

In one aspect, provided herein is a method of identifying a subject having a cancer with a SHP2 gene mutation, the method comprising:

(a) Obtaining a biological sample from a subject; and

(b) Detection is performed and the samples are screened for mutations.

In another aspect, provided herein are methods for screening or identifying subjects having a cancer suitable for treatment with a MEK inhibitor or a dual RAF/MEK inhibitor in combination with an SOS1 inhibitor. For example, the methods are directed to identifying a subject who is likely to respond to the cancer treatments described herein. Also provided are methods for optimizing the efficacy of treatment of a subject having cancer, wherein the treatment comprises administration of a MEK inhibitor or a combination of a dual RAF/MEK inhibitor and a SOS1 inhibitor.

In another aspect, provided herein is a method of detecting the presence of a SOS1 gene mutation associated with a subject having cancer, the method comprising:

(a) Obtaining a biological sample from a subject; and

(b) Detection is performed and the samples are screened for mutations.

In one aspect, provided herein is a method of identifying a subject having a cancer with a SOS1 gene mutation, the method comprising:

(a) Obtaining a biological sample from a subject; and

(b) Detection is performed and the samples are screened for mutations.

In another aspect, provided herein are methods for screening or identifying subjects having cancer suitable for treatment with a MEK inhibitor or dual RAF/MEK inhibitor in combination with an ERK1/2 inhibitor. For example, the methods are directed to identifying a subject who is likely to respond to the cancer treatments described herein. Also provided are methods for optimizing the efficacy of treatment of a subject having cancer, wherein the treatment comprises administration of a MEK inhibitor or a combination of a dual RAF/MEK inhibitor and an ERK1/2 inhibitor.

In another aspect, provided herein is a method of detecting the presence of an ERK1/2 gene mutation associated with a subject having cancer, the method comprising:

(a) Obtaining a biological sample from a subject; and

(b) Detection is performed and the samples are screened for mutations.

In another aspect, provided herein is a method of identifying a subject having a cancer with an ERK1/2 gene mutation, the method comprising:

(a) Obtaining a biological sample from a subject; and

(b) Detection is performed and the samples are screened for mutations.

In another aspect, provided herein are methods for screening or identifying subjects having a cancer suitable for treatment with a MEK inhibitor or dual RAF/MEK inhibitor in combination with a CDK4/6 inhibitor. For example, the methods are directed to identifying a subject who is likely to respond to the cancer treatments described herein. Also provided are methods for optimizing the efficacy of treatment of a subject having cancer, wherein the treatment comprises administration of a MEK inhibitor or a dual RAF/MEK inhibitor in combination with a CDK4/6 inhibitor.

In another aspect, provided herein is a method of detecting the presence of a CDK4/6 gene mutation associated with a subject having cancer, the method comprising:

(a) Obtaining a biological sample from a subject; and

(b) Detection is performed and the samples are screened for mutations.

In another aspect, provided herein is a method of identifying a subject having a cancer with a CDK4/6 gene mutation, the method comprising:

(a) Obtaining a biological sample from a subject; and

(b) Detection is performed and the samples are screened for mutations.

In another aspect, provided herein are methods for screening or identifying subjects having a cancer suitable for treatment with a MEK inhibitor or dual RAF/MEK inhibitor in combination with an AKT inhibitor. For example, the methods are directed to identifying a subject who is likely to respond to the cancer treatments described herein. Also provided are methods for optimizing the efficacy of treatment of a subject having cancer, wherein the treatment comprises administration of a MEK inhibitor or a combination of a dual RAF/MEK inhibitor and an AKT inhibitor.

In another aspect, provided herein is a method of detecting the presence of an AKT gene mutation associated with a subject having cancer, the method comprising:

(a) Obtaining a biological sample from a subject; and

(b) Detection is performed and the samples are screened for mutations.

In another aspect, provided herein is a method of identifying a subject having a cancer with an AKT gene mutation, the method comprising:

(a) Obtaining a biological sample from a subject; and

(b) Detection is performed and the samples are screened for mutations.

In another aspect, provided herein are methods for screening or identifying subjects having a cancer suitable for treatment with a MEK inhibitor or a dual RAF/MEK inhibitor in combination with an mTOR inhibitor. For example, the methods are directed to identifying a subject who is likely to respond to the cancer treatments described herein. Also provided are methods for optimizing the efficacy of treatment of a subject having cancer, wherein the treatment comprises administration of a MEK inhibitor or a combination of a dual RAF/MEK inhibitor and an mTOR inhibitor.

In another aspect, provided herein is a method of detecting the presence of a mutation in an mTOR gene associated with a subject having cancer, the method comprising:

(a) Obtaining a biological sample from a subject; and

(b) Detection is performed and the samples are screened for mutations.

In another aspect, provided herein is a method of identifying a subject having a cancer with a mutation in an mTOR gene, the method comprising:

(a) Obtaining a biological sample from a subject; and

(b) Detection is performed and the samples are screened for mutations.

In another aspect, provided herein are methods for screening or identifying subjects having a cancer suitable for treatment with a MEK inhibitor or dual RAF/MEK inhibitor in combination with a pan-HER inhibitor. For example, the methods are directed to identifying a subject who is likely to respond to the cancer treatments described herein. Also provided are methods for optimizing the efficacy of treatment of a subject having cancer, wherein the treatment comprises administering a MEK inhibitor or a combination of a dual RAF/MEK inhibitor and a pan-HER inhibitor.

In another aspect, provided herein is a method of detecting the presence of a pan-HER gene mutation associated with a subject having cancer, the method comprising:

(a) Obtaining a biological sample from a subject; and

(b) Detection is performed and the samples are screened for mutations.

In another aspect, provided herein is a method of identifying a subject having a cancer with a pan-HER gene mutation, the method comprising:

(a) Obtaining a biological sample from a subject; and

(b) Detection is performed and the samples are screened for mutations.

In another aspect, provided herein are methods for screening or identifying subjects having a cancer suitable for treatment with a MEK inhibitor or a dual RAF/MEK inhibitor in combination with an EGFR inhibitor. For example, the methods are directed to identifying a subject who is likely to respond to the cancer treatments described herein. Also provided are methods for optimizing the efficacy of treatment of a subject having cancer, wherein the treatment comprises administering a MEK inhibitor or a combination of a dual RAF/MEK inhibitor and an EGFR inhibitor.

In another aspect, provided herein is a method of detecting the presence of an EGFR gene mutation associated with a subject having cancer, the method comprising:

(a) Obtaining a biological sample from a subject; and

(b) Detection is performed and the samples are screened for mutations.

In another aspect, provided herein is a method of identifying a subject having cancer with an EGFR gene mutation, the method comprising:

(a) Obtaining a biological sample from a subject; and

(b) Detection is performed and the samples are screened for mutations.

Samples include, but are not limited to, tissue samples (e.g., tumor tissue samples), primary or cultured cells or cell lines, cell supernatants, cell lysates, platelets, serum, plasma, vitreous humor, lymph, synovial fluid, follicular fluid, semen, amniotic fluid, milk, whole blood, blood derived cells, urine, cerebrospinal fluid, saliva, sputum, tears, sweat, mucus, tumor lysates and tissue culture media, tissue extracts, e.g., homogenized tissue, tumor tissue, cell extracts, and combinations thereof. In some embodiments, the sample is serum, blood, urine, or plasma.

Specific mutation status of the SHP2, SOS1, ERK1/2, CDK4/6, AKT, mTOR, pan-HER or EGFR gene in a sample obtained from an individual can be identified by any of a number of methods well known to those skilled in the art. For example, the identification of the mutation may be accomplished by cloning the SHP2, SOS1, ERK1/2, CDK4/6, AKT, mTOR, pan-HER or EGFR gene or portion thereof and sequencing it using techniques well known in the art. Alternatively, the gene sequence may be amplified from genomic DNA, for example using PCR, and the product sequenced. In some embodiments, the testing comprises sequencing. In some embodiments, the test comprises a Polymerase Chain Reaction (PCR). Exemplary assays include, but are not limited to, nucleic acid sequencing (dideoxy and pyrosequencing), real-time PCR with melting curve analysis, and allele-specific PCR with various modes for distinguishing mutant and wild-type sequences. The testing may also include quantitatively or semi-quantitatively determining the amount of mutation of cell free DNA (cfDNA) in the sample.

Examples

In order that the invention described herein may be more fully understood, the following examples are set forth. The examples described in this application are for illustration of the pharmaceutical compositions and methods provided herein and should not be construed in any way to limit their scope.

Example 1 anti-tumor efficacy of Dual RAF/MEK inhibitor VS-6766 and SHP2 inhibitor

Materials and methods

In vitro 3D proliferation assay

KRAS G12C, G D or G12V mutant non-small cell lung cancer (NSCLC) and pancreatic cancer cell lines were grown under 3D conditions. Briefly, 96-well plates were coated with 50. Mu.L Matrigel (100%) and incubated at 37℃and 5% CO ₂ Incubate for 30 minutes to allow Matrigel to cure. Cells were inoculated in 100. Mu.L of 2% Matrigel in medium. After overnight incubation (17-22 hours), cells were treated with VS-6766+/-SHP2i (TNO 155 or RMC-4550) for 7 days. Cell viability was measured using the cell viability CellTiter-Glo assay. Fig. 1A shows an exemplary CellTiter-Glo assay for assessing cell viability of 16 KRAS G12C, G D or G12V mutant cell lines (9 NSCLC and 7 PDACs) grown under 3D conditions in a 7 day assay. IC50 s for VS-6766, TNO155 and RMC-4550 were calculated (FIG. 1B).

And (5) collaborative analysis.

Raw data and metadata files are processed using custom R scripts (custom R-scripts) for individual agents and combined activities. Bliss, loewe, highest Single Agent (HSA) and ZIP synergy analyses were performed to generate a composite synergy score. The abbreviated graph and report is saved for visualization and further analysis. The combined synergistic results of VS-6766+TNO155 or VS-6766+RMC-4550 were summarized using a waterfall plot. Briefly, FIG. 2A shows the operation of cells in a CTG proliferation assay. The raw data and metadata files are processed using custom rscript for individual agents and combined activities. Bliss, loewe, highest Single Agent (HSA) and ZIP synergy analyses were performed to generate a composite synergy score. FIG. 2B shows an example of VS-6766+TNO155 in H2122 cells. Fig. 2C shows a waterfall plot summarizing the combined synergy of VS-6766+ tno155 in a set of KRAS mut NSCLC and PDAC cell lines.

Xenograft tumor mice study

KRAS mutant H2122 NSCLC tumor cells were obtained from ATCC and Balb/c nude mice were obtained from Shanghai Ling Biotechnology Co., ltd (Shanghai Lingchang Biotechnology). By mixing 1x 10 ⁷ Tumor cell suspensions were inoculated subcutaneously into the right flank of recipient mice to initiate tumor challenge. Once the average tumor volume reaches 150-200mm ³ Mice were divided into 4 groups (n=10): vehicle, VS-6766 (0.3 mg/kg PO QD), RMC-4550 (10 mg/kg QD) and VS-6766+RMC-4550. In another group of study, mice were divided into 4 groups (n=10): vehicle, VS-6766 (0.3 mg/kg PO QD), TNO155 (15 mg/kg BID) and VS-6766+TNO155.

Tumor size (mm) was measured weekly during the study period ³ ) And body weight 2 times. At routine monitoring, animals were examined for any effect of tumor growth and treatment on normal behavior, such as motility, food and water consumption (by observation only), weight gain/loss, eye/hair extinction, and any other abnormal effects.

Results

The dose response matrix was used to evaluate the antiproliferative effect of VS-6766 in combination with TNO155 or RMC-4550. The synergy scores were calculated using 4 different methods (Bliss, loewe, HSA and ZIP) in combination. VS-6766, in synergy with TNO155 (FIG. 3A, FIG. 3B) or RMC-4550 (FIG. 4A, FIG. 4B), reduced the viability of a panel of 16 KRAS mutations (G12C, G D and G12V) NSCLC and pancreatic cancer cell lines.

We also investigated whether VS-6766 enhances the in vivo efficacy of the SHP2 inhibitor RMC-4550 in the KRAS mutant H2122NSCLC model (FIG. 5A). As a result, it was found that the combination of VS-6766+RMC-4550 enhanced tumor growth inhibition compared to either single agent alone. Next we studied whether VS-6766 enhances the in vivo efficacy of the SHP2 inhibitor TNO155 in KRAS mutant H2122NSCLC model (fig. 5B). As a result, it was found that the combination of VS-6766+TNO155 enhanced tumor growth inhibition compared to either single agent alone.

These results support clinical assessment of the use of VS-6766 in combination with drugs against SHP2 and potentially establish VS-6766 as a support for the treatment of RAS-driven cancers.

Example 2 anti-tumor efficacy of Dual RAF/MEK inhibitor VS-6766 and SOS1 inhibitor

Materials and methods

In vitro 3D proliferation assay

KRAS G12C, G D or G12V mutant non-small cell lung cancer (NSCLC) and pancreatic cancer cell lines were grown under 3D conditions. Briefly, 96-well plates were coated with 50. Mu.L Matrigel (100%) and incubated at 37℃and 5% CO ₂ Incubate for 30 minutes to allow Matrigel to cure. Cells were inoculated in 100. Mu.L of 2% Matrigel in medium. After overnight incubation (17-22 hours), cells were treated with VS-6766+/-BI-3406 for 7 days. Cell viability was measured using the cell viability CellTiter-Glo assay. Fig. 6A shows an exemplary CellTiter-Glo assay for assessing cell viability of 16 KRAS G12C, G D or G12V mutant cell lines (9 NSCLC and 7 PDACs) grown under 3D conditions in a 7 day assay. IC50 s for VS-6766 and BI-3406 were calculated (FIG. 56).

And (5) collaborative analysis.

Raw data and metadata files are processed using custom R scripts (custom R-scripts) for individual agents and combined activities. Bliss, loewe, highest Single Agent (HSA) and ZIP synergy analyses were performed to generate a composite synergy score. The abbreviated graph and report is saved for visualization and further analysis. The combined synergistic results of VS-6766+BI3406 are summarized using a waterfall plot. Briefly, cells were run in CTG proliferation assay (fig. 7A). The raw data and metadata files are processed using custom rscript for individual agents and combined activities. Bliss, loewe, highest Single Agent (HSA) and ZIP synergy analyses were performed to generate a composite synergy score. The abbreviated graph and report is saved for visualization and further analysis. An example used in this figure is VS-6766+BI-3406 in H2122 cells (FIG. 7B). The waterfall plot summarizes the combined synergistic results of VS-6766+bi-3406 in a panel of KRAS mut NSCLC and PDAC cell lines (fig. 7C).

Xenograft tumor mice study

KRAS mutant H2122 NSCLC tumor cells were obtained from ATCC and Balb/c nude mice were obtained from Shanghai Ling Biotechnology Co., ltd (Shanghai Lingchang Biotechnology). By mixing 1x 10 ⁷ Tumor cell suspensions were inoculated subcutaneously into the right flank of recipient mice to initiate tumor challenge. Once the average tumor volume reaches 150-200mm ³ Mice were divided into 4 groups (n=10): vehicle, VS-6766 (0.3 mg/kg PO QD), BI-3406 (50 mg/kg BID) and VS-6766+BI-3406.

Tumor size (mm) was measured weekly during the study period ³ ) And body weight 2 times. At routine monitoring, animals were examined for any effect of tumor growth and treatment on normal behavior, such as motility, consumption of food and water (by observation only) and weight gain/loss, eye/hair extinction and any other abnormal effects.

Results

The dose response matrix was used to evaluate the antiproliferative effect of the combination of VS-6766 and BI 3406. The synergy scores were calculated using 4 different methods (Bliss, loewe, HSA and ZIP) in combination. VS-6766 has synergistic effects with BI3406, and can reduce the viability of a group of 16 KRAS mutant (G12C, G D and G12V) NSCLC and pancreatic cancer cell lines. FIG. 8A shows an exemplary waterfall graph summarizing the combined synergistic results of VS-6766+BI3406 in a set of KRAS mut NSCLC and PDAC cell lines. For example, VS-6766 in combination with BI3406 may enhance the anti-tumor response of H2122 cells (FIG. 8B).

We also investigated whether VS-6766 enhances the in vivo efficacy of SOS1 inhibitor BI-3406 in KRAS mutant H2122 NSCLC model (FIG. 9). As a result, it was found that the combination of VS-6766+BI-3406 enhanced tumor growth inhibition compared to either single agent alone.

These results support clinical assessment of the use of VS-6766 in combination with drugs against SOS1 and potentially establish VS-6766 as a support for the treatment of RAS-driven cancers.

Example 3 anti-tumor efficacy of Dual RAF/MEK inhibitor VS-6766 and ERK1/2 inhibitors

Materials and methods

In vitro 3D proliferation assay

KRAS G12C, G D or G12V mutant non-small cell lung cancer (NSCLC) and pancreatic cancer cell lines were grown under 3D conditions. Briefly, 96-well plates were coated with 50. Mu.L Matrigel (100%) and incubated at 37℃and 5% CO ₂ Incubate for 30 minutes to allow Matrigel to cure. Cells were inoculated in 100. Mu.L of 2% Matrigel in medium. After overnight incubation (17-22 hours), cells were treated with VS-6766+/-LY-3214996 for 7 days. Cell viability was measured using the cell viability CellTiter-Glo assay. Fig. 10A shows an exemplary CellTiter-Glo assay for assessing cell viability of 16 KRAS G12C, G D or G12V mutant cell lines (9 NSCLC and 7 PDACs) grown under 3D conditions in a 7 day assay. IC50 s for VS-6766 and LY-3214996 were calculated (FIG. 10B).

And (5) collaborative analysis.

Raw data and metadata files are processed using custom R scripts (custom R-scripts) for individual agents and combined activities. Bliss, loewe, highest Single Agent (HSA) and ZIP synergy analyses were performed to generate a composite synergy score. The abbreviated graph and report is saved for visualization and further analysis. The combined synergy of VS-6766+ ly-3214996 is summarized using a waterfall plot. Briefly, cells were run in CTG proliferation assay (fig. 11A). The raw data and metadata files are processed using custom rscript for individual agents and combined activities. Bliss, loewe, highest Single Agent (HSA) and ZIP synergy analyses were performed to generate a composite synergy score. The abbreviated graph and report is saved for visualization and further analysis. An example used in this figure is VS-6766+LY-3214996 in H2122 cells (FIG. 11B). The waterfall plot summarizes the combined synergistic results of VS-6766+LY-3214996 in a panel of KRAS mut NSCLC and PDAC cell lines (FIG. 11C).

Xenograft tumor mice study

KRAS mutant H2122 NSCLC tumor cells were obtained from ATCC and Balb/c nude mice were obtained from Shanghai Ling Biotechnology Co., ltd (Shanghai Lingchang Biotechnology). By mixing 1x 10 ⁷ Tumor cell suspensions were inoculated subcutaneously into the right flank of recipient mice to initiate tumor challenge. Once the average tumor volume reaches 150-200mm ³ Mice were divided into 4 groups (n=10): vehicle, VS-6766 (0.3 mg/kg PO QD), LY-3214996 (60 mg/kg QD) and VS-6766+LY-3214996.

Tumor size (mm) was measured weekly during the study period ³ ) And body weight 2 times. At routine monitoring, animals were examined for any effect of tumor growth and treatment on normal behavior, such as motility, consumption of food and water (by observation only) and weight gain/loss, eye/hair extinction and any other abnormal effects.

Results

The dose response matrix was used to evaluate the antiproliferative effect of the combination of VS-6766 and LY-3214996. The synergy scores were calculated using 4 different methods (Bliss, loewe, HSA and ZIP) in combination. VS-6766 has synergistic effects with LY-3214996, and can reduce the viability of a group of 16 KRAS mutant (G12C, G D and G12V) NSCLC and pancreatic cancer cell lines. FIG. 12A shows an exemplary waterfall plot summarizing the combined synergistic results of VS-6766+LY-3214996 in a set of KRAS mut NSCLC and PDAC cell lines. For example, VS-6766 in combination with LY-3214966 enhanced the anti-tumor response of H2122 cells (FIG. 12B).

We also investigated whether VS-6766 enhances the in vivo efficacy of ERK1/2 inhibitor LY-3214996 in the KRAS mutant H2122 NSCLC model (FIG. 13). As a result, it was found that the combination of VS-6766+LY-3214996 enhanced tumor growth inhibition compared to either single agent alone.

These results support clinical assessment of the use of VS-6766 in combination with drugs against ERK1/2 and potentially establish VS-6766 as a support for the treatment of RAS-driven cancers.

Example 4 anti-tumor efficacy of Dual RAF/MEK inhibitor VS-6766 and CDK4/6 inhibitor

Materials and methods

In vitro 3D proliferation assay

KRAS G12C, G D or G12V mutant non-small cell lung cancer (NSCLC) and pancreatic cancer cell lines were grown under 3D conditions. In another set of experiments, er+ breast cancer cell lines were grown under 3D conditions. Briefly, 96-well plates were coated with 50. Mu.L Matrigel (100%) and incubated at 37℃and 5% CO ₂ Incubate for 30 minutes to allow Matrigel to cure. Cells were inoculated in 100. Mu.L of 2% Matrigel in medium. After overnight incubation (17-22 hours), cells were treated with VS-6766+/-palbociclib or abbe cili for 7 days. Cell viability was measured using the cell viability CellTiter-Glo assay. Fig. 14A shows an exemplary CellTiter-Glo assay for assessing cell viability of 16 KRAS G12C, G D or G12V mutant cell lines (9 NSCLC and 7 PDACs) grown under 3D conditions in a 7 day assay. The IC50 for VS-6766, palbociclib, or abbe cili was calculated (FIG. 14B).

And (5) collaborative analysis.

Raw data and metadata files are processed using custom R scripts (custom R-scripts) for individual agents and combined activities. Bliss, loewe, highest Single Agent (HSA) and ZIP synergy analyses were performed to generate a composite synergy score. The abbreviated graph and report is saved for visualization and further analysis. The combined synergy of VS-6766+ pamoxrib or abbe-cili was summarized using a waterfall plot. Briefly, cells were run in CTG proliferation assay (fig. 15A). The raw data and metadata files are processed using custom rscript for individual agents and combined activities. Bliss, loewe, highest Single Agent (HSA) and ZIP synergy analyses were performed to generate a composite synergy score. The abbreviated graph and report is saved for visualization and further analysis. An example used in this figure is VS-6766+Pabosini in A427 cells (FIG. 15B). The waterfall plot summarizes the combined synergistic results of VS-6766+ palbociclib in a panel of KRAS mut NSCLC and PDAC cell lines (fig. 15C).

Xenograft tumor mice study

KRAS mutant H2122 NSCLC tumor cells were obtained from ATCC and Balb/c nude mice were obtained from Shanghai Ling Biotechnology Co., ltd (Shanghai Lingchang Biotechnology). By mixing 1x 10 ⁷ Subcutaneous inoculation of tumor cell suspensions into recipientsTumor challenge was initiated in the right flank of the body mice. Once the average tumor volume reaches 150-200mm ³ Mice were divided into 4 groups (n=10): vehicle, VS-6766 (0.3 mg/kg PO QD), abeli (25 mg/kg QD) and VS-6766+Abeli.

Tumor size (mm) was measured weekly during the study period ³ ) And body weight 2 times. At routine monitoring, animals were examined for any effect of tumor growth and treatment on normal behavior, such as motility, consumption of food and water (by observation only) and weight gain/loss, eye/hair extinction and any other abnormal effects.

Results

The dose response matrix was used to evaluate the antiproliferative effect of the VS-6766+ palbociclib or abbe cilib combination. The synergy scores were calculated using 4 different methods (Bliss, loewe, HSA and ZIP) in combination. VS-6766, acting synergistically with palbociclib (fig. 16A, 16B) or abeyanili (fig. 17A, 17B), reduced the viability of a panel of 16 KRAS mutations (G12C, G D and G12V) NSCLC and pancreatic cancer cell lines.

We also investigated whether VS-6766 enhanced the in vivo efficacy of the CDK4/6 inhibitor arbelide in the KRAS mutant H2122 NSCLC model (fig. 18). As a result, it was found that the combination of VS-6766+Abeli enhanced tumor growth inhibition compared to either single agent alone.

Next, the dose response matrix was used to evaluate the antiproliferative effect of the VS-6766+ Abeli combination in ER+ breast cancer cell lines. The synergy scores were calculated using 4 different methods (Bliss, loewe, HSA and ZIP) in combination. FIG. 19A shows Bliss, loewe, HSA and ZIP synergy analysis was performed to generate a composite synergy score. VS-6766 has synergistic effects with Abeli and can reduce the viability of a group of 3 ER+ breast cancer cell lines. FIG. 19B shows Bliss synergy scores in MCF7ER+ breast cancer cell lines, and FIG. 19C shows Bliss synergy scores in ZR-75-1ER+ breast cancer cell lines.

These results support clinical assessment of the use of VS-6766 in combination with drugs directed against CDK4/6 and potentially establish VS-6766 as a support for the treatment of RAS-driven cancers.

Example 5 anti-tumor efficacy of Dual RAF/MEK inhibitor VS-6766 with AKT or mTOR inhibitors

Materials and methods

In vitro 3D proliferation assay

KRAS G12C, G D or G12V mutant non-small cell lung cancer (NSCLC) and pancreatic cancer cell lines were grown under 3D conditions. Briefly, 96-well plates were coated with 50. Mu.L Matrigel (100%) and incubated at 37℃and 5% CO ₂ Incubate for 30 minutes to allow Matrigel to cure. Cells were inoculated in 100. Mu.L of 2% Matrigel in medium. After overnight incubation (17-22 hours), cells were treated with VS-6766+/-patatide, M2698 or everolimus for 7 days. Cell viability was measured using the cell viability CellTiter-Glo assay. The CellTiter-Glo assay was used to evaluate the cell viability of 16 KRAS G12C, G D or G12V mutant cell lines (9 NSCLC and 7 PDACs) grown under 3D conditions in a 7 day assay (fig. 20A). IC50 s for VS-6766, patadine, M2698, and everolimus were calculated (FIG. 20B).

And (5) collaborative analysis.

Raw data and metadata files are processed using custom R scripts (custom R-scripts) for individual agents and combined activities. Bliss, loewe, highest Single Agent (HSA) and ZIP synergy analyses were performed to generate a composite synergy score. The abbreviated graph and report is saved for visualization and further analysis. The combined synergy of VS-6766+ patadine, M2698, or everolimus was summarized using a waterfall plot. Briefly, cells were run in CTG proliferation assay (fig. 21A). The raw data and metadata files are processed using custom rscript for individual agents and combined activities. Bliss, loewe, highest Single Agent (HSA) and ZIP synergy analyses were performed to generate a composite synergy score. The abbreviated graph and report is saved for visualization and further analysis. An example used in this figure is VS-6766+M2698 in SW1573 cells (FIG. 21B). The waterfall plot summarizes the combined synergistic results of VS-6766+m2698 in a panel of KRAS mut NSCLC and PDAC cell lines (fig. 21C).

Results

The dose response matrix was used to evaluate the antiproliferative effect of the combination of VS-6766+ patatide, M2698, or everolimus. The synergy scores were calculated using 4 different methods (Bliss, loewe, HSA and ZIP) in combination. VS-6766 synergistically acts with patadine (fig. 22A, 22B), M2698 (fig. 23A, 23B) or everolimus (fig. 24A, 24B) to reduce the viability of a panel of 16 KRAS mutations (G12C, G D and G12V) NSCLC and pancreatic cancer cell lines.

These results support clinical assessment of the use of VS-6766 in combination with drugs directed against AKT/mTOR and potentially establish VS-6766 as a support for the treatment of RAS-driven cancers.

Example 6 anti-tumor efficacy of Dual RAF/MEK inhibitor VS-6766 with pan-HER or EGFR inhibitor

Materials and methods

In vitro 3D proliferation assay

KRAS G12C, G D or G12V mutant non-small cell lung cancer (NSCLC) and pancreatic cancer cell lines were grown under 3D conditions. Briefly, 96-well plates were coated with 50. Mu.L Matrigel (100%) and incubated at 37℃and 5% CO ₂ Incubate for 30 minutes to allow Matrigel to cure. Cells were inoculated in 100. Mu.L of 2% Matrigel in medium. After overnight incubation (17-22 hours), cells were treated with VS-6766+/-afatinib for 7 days. Cell viability was measured using the cell viability CellTiter-Glo assay. The CellTiter-Glo assay was used to evaluate the cell viability of 16 KRAS G12C, G D or G12V mutant cell lines (9 NSCLC and 7 PDACs) grown under 3D conditions in a 7 day assay (fig. 25A). IC50 s for VS-6766 and afatinib were calculated (FIG. 25B).

And (5) collaborative analysis.

Raw data and metadata files are processed using custom R scripts (custom R-scripts) for individual agents and combined activities. Bliss, loewe, highest Single Agent (HSA) and ZIP synergy analyses were performed to generate a composite synergy score. The abbreviated graph and report is saved for visualization and further analysis. The combined synergy of VS-6766+ afatinib was summarized using a waterfall plot. Briefly, cells were run in CTG proliferation assay (fig. 26A). The raw data and metadata files are processed using custom rscript for individual agents and combined activities. Bliss, loewe, highest Single Agent (HSA) and ZIP synergy analyses were performed to generate a composite synergy score. The abbreviated graph and report is saved for visualization and further analysis. An example used in this figure is VS-6766+ afatinib in H2122 cells (FIG. 26B). The waterfall plot summarizes the combined synergistic results of VS-6766+ afatinib in a panel of KRAS mut NSCLC and PDAC cell lines (fig. 26C).

Xenograft tumor mice study

KRAS mutant H2122 NSCLC tumor cells were obtained from ATCC and Balb/c nude mice were obtained from Shanghai Ling Biotechnology Co., ltd (Shanghai Lingchang Biotechnology). By mixing 1x 10 ⁷ Tumor cell suspensions were inoculated subcutaneously into the right flank of recipient mice to initiate tumor challenge. Once the average tumor volume reaches 150-200mm ³ Mice were divided into 4 groups (n=10): vehicle, VS-6766 (0.3 mg/kg PO QD), afatinib (10 mg/kg QD) and VS-6766+afatinib.

EGFR mutant H1975 NSCLC tumor cells were obtained from ATCC, EGFR mutant H1975 octenib resistant NSCLC tumor cells were produced by Wuxi AppTec, and Balb/c nude mice were obtained from Peking Vitolihua laboratory animal technologies Co., ltd (Beijing Vital River Laboratory Animal Technology). By mixing 5x 10 ⁶ Tumor cell suspensions were inoculated subcutaneously into the right flank of recipient mice to initiate tumor challenge. Once the average tumor volume reaches 150-200mm ³ Mice were divided into 4 groups (n=10): vehicle, VS-6766 (0.3 mg/kg PO QD), orientinib (2.5 mg/kg QD) and VS-6766+Orientinib.

Tumor size (mm) was measured weekly during the study period ³ ) And body weight 2 times. At routine monitoring, animals were examined for any effect of tumor growth and treatment on normal behavior, such as motility, consumption of food and water (by observation only) and weight gain/loss, eye/hair extinction and any other abnormal effects.

Results

The dose response matrix was used to evaluate the antiproliferative effect of the combination of VS-6766 and afatinib. The synergy scores were calculated using 4 different methods (Bliss, loewe, HSA and ZIP) in combination. VS-6766 has a synergistic effect with afatinib, reducing the viability of a panel of 16 KRAS mutant (G12C, G D and G12V) NSCLC and pancreatic cancer cell lines (FIG. 27A, FIG. 27B).

We investigated whether VS-6766 enhances the in vivo efficacy of the pan-HER inhibitor afatinib in the KRAS mutant H2122 NSCLC model (FIG. 28). As a result, it was found that the combination of VS-6766+afatinib enhanced tumor growth inhibition compared to either single agent alone.

We also investigated whether VS-6766 enhanced the in vivo efficacy of the EGFR inhibitor of octreotide in EGFR mutant H1975, parental and octreotide resistant NSCLC models (fig. 29, fig. 30). In the H1975 parental model, tumor regression occurred with VS-6766+octtinib, but no tumor regression occurred with either drug alone (fig. 29). Furthermore, an increase in survival was observed in the combination treatment group compared to either single drug alone. In the H1975 octenib resistance model, VS-6766 increased tumor growth inhibition and survival compared to the octenib single agent (FIG. 30).

These results support clinical assessment of the use of VS-6766 in combination with drugs against EGFR, and potentially establish VS-6766 as a support for the treatment of RAS-driven cancers.

Equivalents and scope

In the claims, articles such as "a/an" and "the" may mean one or more than one unless indicated to the contrary or otherwise apparent from the context. Unless indicated to the contrary or otherwise apparent from the context, a claim or specification that includes an "or" between one or more members of a group is considered satisfied if one, more than one, or all of the group members are present, used in, or otherwise relevant to a given product or method. The present invention includes implementations in which exactly one member of the group is present, used in, or otherwise related to a given product or process. The present invention includes embodiments in which more than one or all of the group members are present, used in, or otherwise related to a given product or process.

Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims are introduced into another claim. For example, any claim that is dependent on another claim may be modified to include one or more limitations found in any other claim that is dependent on the same base claim. When elements are presented in a manifest form (e.g., in Markush group (Markush group)), each subset of the elements is also disclosed, and any elements may be removed from the group. It should be understood that, in general, where the invention or aspects of the invention are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist of or consist essentially of such elements and/or features. For simplicity, those embodiments have not been set forth herein exclusively in these words. It should also be noted that the terms "comprising" and "including" are intended to be open-ended and allow for the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values expressed as ranges may employ any particular value or subrange within the range in different embodiments of the invention, reaching one tenth of the unit of the lower limit of the range unless the context clearly dictates otherwise.

This application mentions various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and this specification, the present specification shall control. In addition, any particular embodiment of the invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are considered to be known to those of ordinary skill in the art, they may be excluded even if the exclusion is not explicitly set forth herein. Any particular embodiment of the invention may be excluded from any claim for any reason, whether or not related to the presence of prior art.

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. The scope of the embodiments of the invention described herein is not intended to be limited by the foregoing description, but is instead set forth in the following claims. Those skilled in the art will appreciate that various changes and modifications may be made to the invention without departing from the spirit or scope thereof as defined in the appended claims.

Claims (94)

1. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a) an effective amount of a CDK4/6 inhibitor; and b) an effective amount of a dual RAF/MEK inhibitor, thereby treating the subject.

2. A method according to claim 1, wherein the CDK4/6 inhibitor is GLR2007, roniciclib, RP-CDK4/6, TQB3303, trazoyside, SHR-6390, ly Luo Xili, FCN-437c, azoxystrobin, PF-06873600, XZP-3287, ON-123300, ETH-155008, HEC-80797, JS-104, PF-07220060, RMC-4550, SRX-3177, VS-2370), palbociclib, rebaudinib, letrozole+rebabociclib, or abbe's, or a pharmaceutically acceptable salt thereof.

3. A method according to claim 1 or 2, wherein the CDK4/6 inhibitor is abbe, pamoxnib or rebamiphene, or a pharmaceutically acceptable salt thereof.

4. A method according to any one of claims 1 to 3 wherein the CDK4/6 inhibitor is administered at least once daily.

5. A method according to any one of claims 1 to 4 wherein the CDK4/6 inhibitor is administered once daily.

6. A method according to any one of claims 1 to 4 wherein the CDK4/6 inhibitor is administered twice daily.

7. A method according to any one of claims 1 to 6 wherein the CDK4/6 inhibitor is administered orally.

8. A method according to any one of claims 1 to 7 wherein the CDK4/6 inhibitor is administered at about 1mg to about 1000mg per administration.

9. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a) an effective amount of an SOS1 inhibitor; and b) an effective amount of a dual RAF/MEK inhibitor, thereby treating the subject.

10. The method according to claim 9, wherein the SOS1 inhibitor is BMS-SCH, SDGR5, BI-3406, BAY-293, RMC-5845, SDGR5 or BI-1701963, or a pharmaceutically acceptable salt thereof.

11. The method according to claim 9 or 10, wherein the SOS1 inhibitor is SDGR-5, BI-3406 or BI-1701963, or a pharmaceutically acceptable salt thereof.

12. The method according to any one of claims 9-11, wherein the SOS1 inhibitor is administered at least once daily.

13. The method according to any one of claims 9-12, wherein the SOS1 inhibitor is administered once daily.

14. The method according to any one of claims 9-12, wherein the SOS1 inhibitor is administered twice daily.

15. The method according to any one of claims 9-14, wherein the SOS1 inhibitor is administered orally.

16. The method according to any one of claims 9-15, wherein the SOS1 inhibitor is administered at about 1mg to about 1000mg per administration.

17. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a) an effective amount of an ERK1/2 inhibitor; and b) an effective amount of a dual RAF/MEK inhibitor, thereby treating the subject.

18. The method according to claim 17, wherein the ERK1/2 inhibitor is AZ6197, BI ERKi, CC-90003, erat-007, HMPL-295, IPN-ERK, KO-947, LTT462, SCH772984, TK216, ASTX-029, HH-2710, LY-3214996, ulitinib, ASN-007, ATG-017, BPI-27336, JSI-1187, MK-8353, JRP-890 or JRF-108, or a pharmaceutically acceptable salt thereof.

19. The method of claim 17 or 18, wherein the ERK1/2 inhibitor is LY-3214996, or a pharmaceutically acceptable salt thereof.

20. The method according to any one of claims 17-19, wherein the ERK1/2 inhibitor is administered at least once daily.

21. The method according to any one of claims 17-20, wherein the ERK1/2 inhibitor is administered once daily.

22. The method according to any one of claims 17-20, wherein the ERK1/2 inhibitor is administered twice daily.

23. The method according to any one of claims 17-22, wherein the ERK1/2 inhibitor is administered orally.

24. The method according to any one of claims 17-23, wherein the ERK1/2 inhibitor is administered at about 1mg to about 1000mg per administration.

25. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a) an effective amount of an SHP2 inhibitor; and b) an effective amount of a dual RAF/MEK inhibitor, thereby treating the subject.

26. The method according to claim 25, wherein the SHP2 inhibitor is erat-601, TNO-155, SHP099, RMC-4630, RMC-4550, IACS-13909, JAB-3068, JAB-3312, rle-1971, BBP-398, HBI-2376 or ICP-189, BR790, ETS-001, PF-07284892, RX-SHP2i, SH3809, TAS-ASTX, X-37-SHP2, or a pharmaceutically acceptable salt thereof.

27. The method according to claim 25 or 26, wherein the SHP2 inhibitor is JAB-3068, RMC-4630, TNO-155, JAB-3312, rli-1971, BBP-398, HBI-2376, ICP-189 or RMC-4550, or a pharmaceutically acceptable salt thereof.

28. The method according to any one of claims 25-27, wherein the SHP2 inhibitor is administered at least once daily.

29. The method according to any one of claims 25-28, wherein the SHP2 inhibitor is administered once daily.

30. The method according to any one of claims 25-28, wherein the SHP2 inhibitor is administered twice daily.

31. The method according to any one of claims 25-30, wherein the SHP2 inhibitor is administered orally.

32. The method according to any one of claims 25-31, wherein the SHP2 inhibitor is administered at about 1mg to about 1000mg per administration.

33. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a) an effective amount of an AKT inhibitor; and b) an effective amount of a dual RAF/MEK inhibitor, thereby treating the subject.

34. The method according to claim 33, wherein the AKT inhibitor is capigaservib, patatide, LY-2503029, afuresertib hydrochloride, COTI-2, miranservib mesylate, MK-2206, MK-2206+ semtinib sulfate, ONC-201, PTX-200, TAS-117, trimetinib dimethyl sulfoxide + jeponatide, ARQ-751, AT-13148, M2698, ALM-301, BAY-1125976, borussertib, DC-120, FXY-1, JRP-890, KS-99, NISC-6, RX-0201, or RX-0301, or a pharmaceutically acceptable salt thereof.

35. The method according to claim 33 or 34, wherein the AKT inhibitor is M2698 or patatine, or a pharmaceutically acceptable salt thereof.

36. The method according to any one of claims 33-35, wherein the AKT inhibitor is administered at least once daily.

37. The method according to any one of claims 33-36, wherein the AKT inhibitor is administered once daily.

38. The method according to any one of claims 33-36, wherein the AKT inhibitor is administered twice daily.

39. The method according to any one of claims 33-38, wherein the AKT inhibitor is administered orally.

40. The method according to any one of claims 33-39, wherein the AKT inhibitor is administered at about 1mg to about 1000mg per administration.

41. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a) an effective amount of an mTOR inhibitor; and b) an effective amount of a dual RAF/MEK inhibitor, thereby treating the subject.

42. The method according to claim 41, wherein the mTOR inhibitor is everolimus, zortress, sirolimus, temsirolimus, albumin-bound sirolimus, dactolisib tosylate, onatasertib, DTRMWXHS-12+ everolimus+pomalidomide, bimiralisib, CC-115, monetel, sha Pase, sirolimus, valdecolonite, dierotigotine, FP-208, HEC-68498, LXI-15029, ME-344, PTX-367, WXFL-10030390, XP-105, paclitaxel+sirolimus+tamsulosin, AL-58805, AL-58922, AUM-302, CA-102, CA-103, CT-PQF-529, DHM-25, QFT-1518, NSC-765844, omipalisib, OSU-53, OT-043, PQR-514, pramipexole mesylate, QR-213, RMC-5552, SN-202, OSI-965, TAM-03, or a pharmaceutically acceptable salt thereof.

43. The method according to claim 41 or 42, wherein the mTOR inhibitor is everolimus, or a pharmaceutically acceptable salt thereof.

44. The method according to any one of claims 41-43, wherein the mTOR inhibitor is administered at least once daily.

45. The method according to any one of claims 41-44, wherein the mTOR inhibitor is administered once daily.

46. The method according to any one of claims 41-44, wherein the mTOR inhibitor is administered twice daily.

47. The method according to any one of claims 41-46, wherein the mTOR inhibitor is administered orally.

48. The method according to any one of claims 41-47, wherein the mTOR inhibitor is administered at about 1mg to about 1000mg per administration.

49. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a) an effective amount of a pan-HER inhibitor; and b) an effective amount of a dual RAF/MEK inhibitor, thereby treating the subject.

50. The method of claim 49, wherein the pan-HER inhibitor is ZW49, PB 357, MP 0274, VRN 07, BDTX 189, saprotinib, zetolizumab, wave Ji Tini, mo Bo tib, valitinib, pyrroltinib, lapatinib, afatinib, lenatinib, or dacatinib, or a pharmaceutically acceptable salt thereof.

51. The method of claim 49 or 50, wherein the pan-HER inhibitor is saprotinib, zetuzumab, boscalid Ji Tini, mo Bo tinib, valitinib, pyrroltinib, lapatinib, afatinib, lenatinib, or dacatinib, or a pharmaceutically acceptable salt thereof.

52. The method according to any one of claims 49-51, wherein the pan-HER inhibitor is administered at least once daily.

53. The method of any one of claims 49-52, wherein the pan-HER inhibitor is administered once daily.

54. The method according to any one of claims 49-52, wherein the pan-HER inhibitor is administered twice daily.

55. The method according to any one of claims 49-54, wherein the pan-HER inhibitor is administered orally.

56. The method of any one of claims 49-55, wherein the pan-HER inhibitor is administered at about 1mg to about 1000mg per administration.

57. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a) an effective amount of an EGFR inhibitor; and b) an effective amount of a dual RAF/MEK inhibitor, thereby treating the subject.

58. A method according to claim 57, wherein the EGFR inhibitor is doxorubicin + erlotinib, votuximab + zatuximab, evelutinib (abvirtinib) (e.g., evelutinib maleate), ABP-1119, ABP-1130, afatinib (e.g., afatinib dimaleate), AG-101, AL-6802, almitinib (almonetinib) (e.g., ametinib mesylate), evelutinib (Evelutinib maleate), evelutinib (Evelutinib acetate) AM-105, amelimumab, E Mo Tuoshan antibody, AMX-3009, APL-1898, ASK-120067, AST-2818, BBT-176, BDTX-189, BEBT-108, BEBT-109, BH-2922, BLU-4810, BMX-002, BO-1978, BPI-15086, BPI-7711, buntinib, C-005, cetuximab, CK-101 CLM-29, CLM-3, CMAB-017, CR-13626, CSHEGF-29, D-0316, D2C7-it+pvsripo, dabrafenib mesylate+panitumumab+trimetinib dimethyl sulfoxide, daccotinib, DBPR-112, rituximab, DGD-1202, doxitinib (e.g., doxitinib mesylate), DZD-9008, EO-1001, ai Peiti ni, erlotinib (e.g., erlotinib hydrochloride), ES-072, FCN-411, FHND-9041, FLAG-001, FLAG-003, fmpl-2, GB-263, GC-1118A, gefitinib, GS-03+octtinib, HA-12128, HMPL-309, HMPL-813, HS-627, icotinib (e.g., icotinib hydrochloride) JMT-101, JRF-103, JZB-29, KBP-5209, KNP-501, KU-004, lapatinib (e.g., lapatinib ditosylate), lagrantinib, razitinib, lifrafenib (e.g., lifrafenib maleate), MCLA-129, MCLA-158, MDC-22, mo Bo tinib, mRX-7, MTX-211, MVC-101, naquotinib (e.g., naquotinib mesylate), naquotinib (e.g., nazatinib mesylate), cetuximab, lenatinib, nimustinab, NRC-2694, NT-004, NT-113, OBX-1012, omatinib (e.g., omatinib hydrochloride), octenib (e.g., octenib mesylate), panitumumab, PB-357, lamitinib, and pharmaceutical compositions containing the same wave Ji Tini, pyrroltinib, QL-1105, QL-1203, RXDX-105, SAH-EJ1, saprotinib, SCT-200, selatinib (e.g., selatinib di-p-toluenesulfonate), cerotinib, SKLB-1028, SKLB-1206, SPH-118811, SYN-004, TAS-6417, tervaltinib (tervaltinib) (e.g., tervaltinib p-toluenesulfonate), TGRX-360, toxib mab, TQB-3804, UBP-1215, vandetanib, varlitinib, VRN-071918, VRN-6, WBP-297, WJ-13404, WSD-0922, XZP-5809, inlittinib, YZJ-0318, ZNE-4, ZLitinib, ZR-2002, ZSP-0391, ORIC-114, JS-2087 b, 111, LL-191, BI-4020 or Y-2476568, or a pharmaceutically acceptable salt thereof.

59. The method of claim 57 or 58, wherein the EGFR inhibitor is afatinib or octeninib, or a pharmaceutically acceptable salt thereof.

60. The method according to any one of claims 57-59, wherein the EGFR inhibitor is administered at least once daily.

61. The method according to any one of claims 57-60, wherein the EGFR inhibitor is administered once daily.

62. The method according to any one of claims 57-60, wherein the EGFR inhibitor is administered twice daily.

63. The method according to any one of claims 57-62, wherein the EGFR inhibitor is administered orally.

64. The method of any one of claims 57-63, wherein the EGFR inhibitor is administered at about 1mg to about 1000mg per administration.

65. The method according to any one of claims 1-64, wherein the dual RAF/MEK inhibitor is a compound of formula (I):

66. the method according to claim 65, wherein the dual RAF/MEK inhibitor is a compound of formula (I):

67. the method according to claim 65, wherein the dual RAF/MEK inhibitor is a potassium salt of the compound of formula (I).

68. The method according to any one of claims 1-67, wherein the dual RAF/MEK inhibitor is administered orally to the subject.

69. The method according to any one of claims 1-68, wherein the dual RAF/MEK inhibitor is administered twice a week.

70. The method according to any one of claims 1-69, wherein the dual RAF/MEK inhibitor is administered at a dose of 0.5mg to about 10mg per administration.

71. The method according to claim 70, wherein the dual RAF/MEK inhibitor is dosed at 3.2mg per administration.

72. The method according to claim 70, wherein the dual RAF/MEK inhibitor is dosed at 4mg per administration.

73. The method according to any one of claims 1-72, wherein the dual RAF/MEK inhibitor is administered as a cycle comprising administering the dual RAF/MEK inhibitor for three weeks followed by discontinuing the administration of the dual RAF/MEK inhibitor for one week.

74. The method according to any one of claims 1-73, wherein the cancer is lung adenocarcinoma, non-small cell lung carcinoma, colorectal carcinoma, endometrioid carcinoma, bladder urothelial carcinoma, breast invasive lobular carcinoma, cervical squamous cell carcinoma, cutaneous melanoma, cervical adenocarcinoma, hepatocellular carcinoma, pancreatic carcinoma, bipolar pleural mesothelioma, renal clear cell carcinoma, gastric adenocarcinoma, tubular gastric adenocarcinoma, uterine sarcoma, or uterine malignancy mixed Mullerian tumor.

75. The method according to any one of claims 1-73, wherein the cancer is pancreatic cancer, gynaecological cancer (e.g., cervical cancer, ovarian cancer, uterine cancer, vaginal cancer, endometrial cancer or vulvar cancer), liver cancer, prostate cancer, mesothelioma, breast cancer, bladder cancer, melanoma, lung cancer, colorectal cancer, thyroid cancer, glioblastoma or renal cancer.

76. The method according to any one of claims 1-73, wherein the cancer is melanoma, lung cancer, colorectal cancer, ovarian cancer, thyroid cancer, glioblastoma, or renal cancer.

77. A method according to claim 76, wherein said lung cancer is non-small cell lung cancer.

78. A method according to claim 76, wherein said lung cancer is metastatic non-small cell lung cancer.

79. The method according to claim 76, wherein the melanoma is unresectable melanoma.

80. The method according to claim 76, wherein the melanoma is metastatic melanoma.

81. The method according to claim 76, wherein the cancer is colorectal cancer.

82. The method according to claim 76, wherein the cancer is ovarian cancer.

83. The method according to any one of claims 1-82, wherein the cancer is identified as having a RAS mutation.

84. The method according to any one of claims 1-83, wherein the cancer is identified as having a KRAS, NRAS or HRAS mutation.

85. The method of claim 84, wherein the KRAS mutation is a mutation in KRAS G12V, KRAS G12D, KRAS G12A, KRAS G12R, KRAS G12S or KRAS G12C.

86. The method of claim 84, wherein the KRAS mutation is a mutation in KRAS G13V, KRAS G13D, KRAS G13A, KRAS G13R, KRAS G13S, KRAS G13E, KRAS G12 dup, or KRAS G13C.

87. The method of claim 84, wherein the KRAS mutation is a mutation in KRAS Q61H, KRAS Q61K, KRAS Q61L, KRAS Q61R, KRAS Q61P or KRAS Q61E.

88. The method according to any one of claims 1-87, wherein the cancer is identified as having a RAF mutation.

89. The method according to any one of claims 1-88, wherein the cancer is identified as having a BRAF, ARAF or CRAF mutation.

90. The method according to claim 89, wherein the BRAF mutation is a BRAF V600 mutation.

91. The method according to any one of claims 1-90, wherein the cancer is identified as having a MEK1 and/or MEK2 mutation.

92. The method of any one of claims 1-91, wherein the cancer is identified as having NF1 alterations, KRAS amplification and/or NRAS amplification.

93. The method according to any one of claims 1-92, wherein the cancer is identified as having positive phosphorylated ERK protein expression (e.g. ≡10%, ≡20% or ≡30% cells) by immunohistochemical detection.

94. The method according to any one of claims 1-93, wherein the cancer is identified as having an EGFR change.