US20210401859A1 - Methods of treating cancer in biomarker-identified patients with non-covalent inhibitors of cyclin-dependent kinase 7 (cdk7) - Google Patents

Methods of treating cancer in biomarker-identified patients with non-covalent inhibitors of cyclin-dependent kinase 7 (cdk7) Download PDF

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US20210401859A1
US20210401859A1 US17/289,873 US201917289873A US2021401859A1 US 20210401859 A1 US20210401859 A1 US 20210401859A1 US 201917289873 A US201917289873 A US 201917289873A US 2021401859 A1 US2021401859 A1 US 2021401859A1
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John Graeme Hodgson
Liv Helena Johannessen
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Syros Pharmaceuticals Inc
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Definitions

  • the present invention features, inter alia, diagnostic methods for identifying cancer patients for treatment with a non-covalent CDK7 inhibitor described herein (i.e., diagnostic methods for selecting a patient for treatment) and methods for treating identified patients with such an inhibitor, either alone or in combination with one or more additional therapeutic agents (e.g., a second anti-cancer agent), as described further below.
  • the diagnostic methods include a step of identifying a patient suffering from a cancer that is likely to respond well to treatment with a non-covalent CDK7 inhibitor represented by structural Formula (I), (Ia), a species thereof, or a specified form thereof, as shown and described further below.
  • the treatment methods include a step of administering such a non-covalent CDK7 inhibitor to an identified patient, whose response can be, for example, significant tumor growth inhibition (TGI; e.g., more than about 80-90% TGI and/or continued tumor suppression for a period of time after cessation of treatment).
  • TGI tumor growth inhibition
  • the present invention encompasses methods in which a patient is only diagnosed as being a good candidate for treatment (i.e., identified for treatment), methods in which a patient who has been determined to be a good candidate for treatment (e.g., previously identified) is treated, and methods requiring that a patient be both diagnosed and treated as described herein.
  • the diagnostic methods that identify a patient for treatment include a step of analyzing one or more of the biomarkers described herein in a biological sample obtained from the patient by determining, having determined, or receiving information concerning the state of the biomarker.
  • the biomarker is analyzed to determine: whether it is present and/or in what amount (e.g., analyzed for a genetic deletion or amplification (e.g., copy number variation (CNV)); its location (e.g., chromosomal translocation); its sequence (i.e., the analysis can include determining whether the gene is present in wild type form or includes a mutation); whether it includes an epigenetic modification (e.g., histone and/or DNA methylation or histone acetylation); whether it is associated with a super-enhancer (SE) or a SE of a certain strength; its level of expression (as evidenced by, for example, the level of transcribed RNA (e.g., primary RNA or mRNA)); and/or whether
  • the state of a biomarker can be assessed by examining any one or more of the features just listed, and when we refer to “analyzing a/the biomarker,” we mean analyzing one or more of these features (i.e., sequence, copy number, association with a SE, a level of RNA expression, and so forth, as provided above).
  • an RB1 gene is, for example, absent in a biological sample, contains a mutation (e.g., a mutation predisposing a patient to cancer), is translocated, has a CNV (copy number alteration (CNA)), bears an epigenetic modification, is associated with a super-enhancer (SE), is overexpressed or under-expressed (as evidenced by, for example, its level of RNA (e.g., primary RNA or mRNA), and/or encodes a protein with a level of expression or activity that is above or below a predetermined threshold level.
  • CNV copy number alteration
  • SE super-enhancer
  • each feature analyzed can be determined to be equal to or above a pre-determined threshold level or equal to or below a pre-determined threshold level, as described further below.
  • a biomarker selected from the genes BRAF, c-myc (also known as MYC), CDK1, CDK2, CDK4, CDK6, CDK17, CDK18, CDK19, CCNA1, CCNB1, ESR-1, FGFR1, PIK3CA, or certain genes encoding an E2F pathway member (E2F1, E2F2, E2F3, E2F4, E2F5, E2F6, E2F7, E2F8, CCND1, CCND2, CCND3, CCNE1, or CCNE2; see also the Table below), or the proteins encoded thereby, by determining, having determined, and/or receiving information that the state of such a biomarker, as evidenced by a feature just described (e.g., RNA level) is equal to or
  • a biomarker selected from the genes BCL2-like 1, CDK7, CDK9, CDKN2A, and RB (also known as RB1 or another E2F pathway member, such as RBL1, RBL2, CDKN2A, CDKN2B, CDKN2C, CDKN2D, CDKN1A, CDKN1B, CDKN1C, and FBXW7), or the proteins encoded thereby, by determining, having determined, and/or receiving information that the state of such biomarker is equal to or below (e.g., below) a pre-determined threshold level.
  • the proteins encoded by the genes just listed as useful biomarkers in the present methods are known in the art.
  • BRAF encodes B-Raf
  • c-myc encodes MYC
  • CCNE1 encodes cyclin E1 (see Koff et al., Cell 66:1217-1228, 1991)
  • FGFR1 encodes FGFR1, a cell surface membrane receptor with tyrosine kinase activity
  • RB encodes pRB, which binds to the activator domain of activator E2F
  • BCL2-like 1 encodes BCL-xL, a transmembrane protein in mitochondria
  • CDK7 encodes CDK7
  • CDK9 encodes CDK9
  • PIK3CA encodes the p110 ⁇ protein (a catalytic subunit of the class I PI3-kinases)
  • CDKN2A encodes p16 and p14arf.
  • the treatment methods of the invention and corresponding “uses” include administering, or the use of, a compound of Formula (I), any of which may be included in a pharmaceutically acceptable composition and administered, e.g., by a route and regimen described herein, to a patient identified as described herein.
  • a compound of Formula (I) any of which may be included in a pharmaceutically acceptable composition and administered, e.g., by a route and regimen described herein, to a patient identified as described herein.
  • Compounds useful in the present methods have structural Formula (I):
  • R 1 is methyl or ethyl
  • R 2 is methyl or ethyl
  • R 3 is 5-methylpiperidin-3-yl, 5,5-dimethylpiperidin-3-yl, 6-methylpiperdin-3-yl, or 6,6-dimethylpiperidin-3-yl, wherein one or more hydrogen atoms in R 3 is optionally replaced by deuterium
  • R 4 is —CF 3 or chloro.
  • a compound of Formula (I) or in the pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer, isotopic form, or other specified form thereof (i) IV is methyl and R 2 is methyl or (ii) R 1 is methyl and R 2 is ethyl. In other embodiments, R 1 is ethyl and R 2 is ethyl. In some aspects of any one of these embodiments, R 4 is —CF 3 . In other aspects of any one of these embodiments, R 4 is chloro.
  • R 3 is 5-methylpiperidin-3-yl
  • R 3 is 5,5-dimethylpiperidin-3-yl
  • R 3 is 6-methyl-piperdin-3-yl
  • R 3 is 6,6-dimethylpiperidin-3-yl, wherein one or more hydrogen atoms in R 3 is optionally replaced by deuterium.
  • a compound of Formula (I) can have structural Formula (Ia):
  • R 1 is methyl and R 2 is methyl or (ii) R 1 is methyl and R 2 is ethyl. In other embodiments, R 1 is ethyl and R 2 is ethyl.
  • R 4 is —CF 3 . In other embodiments, in a compound of Formula (Ia) or a specified form thereof, R 4 is chloro.
  • a compound of Formula (I) or (Ia) is:
  • the invention encompasses methods and the use of pharmaceutically acceptable salts, solvates (e.g., hydrates), tautomers, isotopic forms or other specified forms of any one of the three foregoing compounds.
  • the compound is
  • the invention also encompasses solvates (e.g., hydrates), tautomers, isotopic forms or other specified forms of the foregoing compound.
  • solvates e.g., hydrates
  • tautomers e.g., tautomers
  • isotopic forms one or more hydrogen atoms in R 3 is replaced with deuterium.
  • none of the hydrogen atoms of a compound e.g., none of the hydrogen atoms in R 3
  • Any compound of Formula (I), (Ia), or a species thereof can be of a “specified form,” by which we mean a salt, solvate (e.g., hydrate), stereoisomer (or mixture thereof), tautomer, or isotopic form of a compound of Formula (I), (Ia), or a species thereof. Also within the meaning of “specified form” are forms of a compound that manifest a combination of the attributes, features, or properties of a salt, solvate, stereoisomer, tautomer, or isotopic form.
  • the methods and uses of the invention can be carried out with a salt that has been solvated (e.g., a hydrated) or a salt of a stereoisomer, tautomer, or isotopic form of a compound of Formula I, I(a), or a species thereof; with a solvate (e.g., hydrate) containing a salt, stereoisomer, tautomer, or isotopic form of a compound of Formula I, I(a), or a species thereof; with a stereoisomer of a compound of Formula I, I(a), or a species thereof that is in the form of a salt or solvate (e.g., hydrate) or is a tautomer or isotopic form of a compound of Formula I, I(a), or a species thereof, with a tautomer of a compound of Formula I, I(a), or a species thereof that is in the form of a salt or solvate (e.g., hydrate) or that is
  • the invention features treatment methods including a step of administering a compound of structural Formula (I), or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer, or isotopic form thereof, optionally within a pharmaceutical composition, wherein R′, R 2 , R 3 , and R 4 are as defined herein, in treating cancer in a selected patient, wherein the patient has been determined to have a cancer in which: (a) a gene selected from RB1, RBL1, RBL2, CDKN2A, CDKN2B, CDKN2C, CDKN2D, CDKN1A, CDKN1B, CDKN1C, and FBWX7 is mutated, is genetically deleted, contains an epigenetic alteration, is translocated, is transcribed at a level equal to or below a pre-determined threshold, or encodes a protein that is translated at a level equal to or below a pre-determined threshold or has decreased activity relative to a reference standard;
  • the cancer is a blood cancer, preferably an acute myeloid leukemia (AML), a breast cancer, preferably a triple negative breast cancer (TNBC) or a hormone receptor positive (HR+) breast cancer, an osteosarcoma or Ewing's sarcoma, fallopian tube cancer, a GI tract cancer, preferably colorectal cancer, a glioma, a lung cancer, preferably small cell or non-small cell lung cancer, melanoma, an ovarian cancer, preferably a high grade serous ovarian cancer, epithelial ovarian cancer, or clear cell ovarian cancer, a pancreatic cancer, a primary peritoneal cancer, prostate cancer, retinoblastoma, or a squamous cell cancer of the head or neck.
  • AML acute myeloid leukemia
  • TNBC triple negative breast cancer
  • HR+ hormone receptor positive
  • fallopian tube cancer a GI tract cancer
  • colorectal cancer preferably colorectal cancer
  • the patient may have such a cancer and can be treated as described herein when it has been determined that, in a biological sample obtained from the patient, Bcl2-like 1 is mutated, contains an epigenetic alteration, is translocated, is transcribed at a level equal to or below a pre-determined threshold, or encodes a BCL-xL protein that is translated at a level equal to or below a pre-determined threshold or has decreased activity relative to a reference standard, preferably wherein a level of Bcl2-like 1 mRNA in the cancer is equal to or below the pre-determined threshold level.
  • such a patient can be one who has undergone, is presently undergoing, or is prescribed treatment with a Bcl-2 inhibitor, as known in the art and/or described herein.
  • the Bcl-2 inhibitor is venetoclax and the patient has a breast cancer (e.g., TNBC); a blood cancer (e.g., AML); an ovarian cancer (e.g., HGSOC); or a lung cancer (e.g., SCLC or NSCLC).
  • the patient may have such a cancer and can be treated as described herein when it has been determined that, in a biological sample obtained from the patient: (a) RB1 or CDKN2A is mutated, contains an epigenetic alteration, is translocated, is transcribed at a level equal to or below a pre-determined threshold, or encodes a protein that is translated at a level equal to or below a pre-determined threshold or has decreased activity relative to a reference standard, preferably wherein RB1 or CDKN2A mRNA, preferably RB1 mRNA, is equal to or below the pre-determined threshold; and/or (b) CDK6, CCND2, or CCNE1 is mutated, has a copy number alteration, contains an epigenetic alteration, is translocated, transcribed at a level equal to or above a pre-determined threshold, or encodes a protein that is translated at a level equal to or above a pre-determined threshold or has increased activity relative to a reference standard,
  • Such a patient can be one who has undergone, is presently undergoing, or is prescribed treatment with a selective estrogen receptor modulator (SERM; e.g., tamoxifen, raloxifene, or toremifene), a selective estrogen receptor degrader (SERD; e.g., fulvestrant), a PARP inhibitor (e.g., olaparib or niraparib); or a platinum-based therapeutic agent (e.g., cisplatin, oxaliplatin, nedaplatin, carboplatin, phenanthriplatin, picoplatin, satraplatin (JM216).
  • SERM selective estrogen receptor modulator
  • SELD selective estrogen receptor degrader
  • PARP inhibitor e.g., olaparib or niraparib
  • platinum-based therapeutic agent e.g., cisplatin, oxaliplatin, nedaplatin, carboplatin, phenan
  • the patient treated with a SERM or SERD may have an HR+ breast cancer
  • the patient treated with a PARP inhibitor may have a TNBC or a Her2 + /ER ⁇ /PR ⁇ breast cancer, fallopian tube cancer, glioma, ovarian cancer (e.g., an epithelial ovarian cancer), or primary peritoneal cancer
  • the patient treated with a platinum-based therapeutic agent may have an ovarian cancer.
  • the patient can be one who has undergone, is presently undergoing, or is prescribed treatment with a BET inhibitor such as ABBV-075, BAY-299, BAY-1238097, BMS-986158, CPI-0610, CPI-203, FT-1101, GS-5829, GSK-2820151, GSK-525762, I-BET151, I-BET762, INCB054329, JQ1, MS436, OTX015, PFI-1, PLX51107, RVX2135, TEN-010, ZEN-3694, or a compound disclosed in U.S.
  • a BET inhibitor such as ABBV-075, BAY-299, BAY-1238097, BMS-986158, CPI-0610, CPI-203, FT-1101, GS-5829, GSK-2820151, GSK-525762, I-BET151, I-BET762, INCB054329, JQ1, MS436, OTX015, PFI-1, PLX
  • a patient who has undergone, is presently undergoing, or is prescribed treatment with a CDK4/6 inhibitor has a breast cancer, preferably a TNBC or an estrogen receptor-positive (ER + ) breast cancer, a pancreatic cancer, or a squamous cell cancer of the head or neck; with a FLT3 inhibitor has a blood cancer, preferably AML; with a BET inhibitor has a breast cancer, preferably TNBC, a blood cancer, preferably AML, Ewing's sarcoma, or an osteosarcoma.
  • a CDK4/6 inhibitor has a breast cancer, preferably a TNBC or an estrogen receptor-positive (ER + ) breast cancer, a pancreatic cancer, or a squamous cell cancer of the head or neck
  • a FLT3 inhibitor has a blood cancer, preferably AML
  • a BET inhibitor has a breast cancer, preferably TNBC, a blood cancer, preferably AML, Ewing's sarcoma, or an osteo
  • the patient can be one who has undergone, is presently undergoing, or is prescribed treatment with a Bcl-2 inhibitor such as APG-1252, APG-2575, BP1002 (prexigebersen), the antisense oligonucleotide known as oblimersen (G3139), S55746/BCL201, or venetoclax; a CDK9 inhibitor such as alvocidib/DSP-2033/flavopiridol, AT7519, AZD5576, BAY1251152, BAY1143572, CYC065, nanoflavopiridol, NVP2, seliciclib (CYC202), TG02, TP-1287, VS2-370 or voruciclib (formerly P1446A-05); a hormone receptor (e.g., estrogen receptor) degradation agent, such as fulvestrant;
  • a hormone receptor e.g., estrogen receptor
  • a platinum-based therapeutic agent such as cisplatin, oxaliplatin, nedaplatin, carboplatin, phenanthriplatin, picoplatin, satraplatin (JM216), or triplatin tetranitrate
  • a CDK4/6 inhibitor such as BPI-1178, G1T38, palbociclib, ribociclib, ON 123300, trilaciclib, or abemaciclib
  • a MEK inhibitor such as trametinib
  • a phosphoinositide 3-kinase (PI3 kinase) inhibitor optionally of Class I (e.g., Class IA) and/or optionally directed against a specific PI3K isoform, such as idelalisib, copanlisib, duvelisib, or alpelisib; or capecitabine.
  • the second agent is selected from a Bcl-2 inhibitor such as venetoclax, a PARP inhibitor such as olaparib or niraparib, a platinum-based anti-cancer agent such as carboplatin or oxaliplatin, a taxane such as paclitaxel, a CDK4/6 inhibitor such as palbociclib, ribociclib, abemaciclib, or trilaciclib, a selective estrogen receptor modulator such as tamoxifen, and a selective estrogen receptor degrader such as fulvestrant.
  • a Bcl-2 inhibitor such as venetoclax
  • a PARP inhibitor such as olaparib or niraparib
  • a platinum-based anti-cancer agent such as carboplatin or oxaliplatin
  • a taxane such as paclitaxel
  • CDK4/6 inhibitor such as palbociclib, ribociclib, abemaciclib, or trilaciclib
  • kits that include a compound of Formula I, I(a), a species thereof, or a specified form thereof, and instructional material (e.g., a product insert) that describes a suitable/identified patient, methods of identifying such a patient for treatment (e.g., by any one of the diagnostic stratification methods described herein for analyzing a biomarker), and/or instructions for administering the compound of Formula I, I(a), a species thereof, or a specified form thereof, alone or in combination with at least one other therapeutic agent (e.g., an additional/second anti-cancer therapeutic including any one or more of the second agents described herein).
  • the kits of the invention can also include the second agent (e.g., an anti-cancer agent), including any one or more of the second agents described herein and instructions for use in a population of patients identified as described.
  • FIG. 1 is a table depicting the inhibitory and dissociation constants and selectivity of the indicated compounds (three compounds of the invention and four comparators) against CDK2, CDK7, CDK9, and CDK12.
  • FIG. 2 is a line graph depicting changes in tumor volume (mm 3 ) over time (days) in a palbociclib-resistant HR+BC PDX model (ST1799), as described in the Examples below.
  • FIG. 3 is a line graph depicting tumor volume (mm 3 ) over time (days) in the palbociclib- and fulvestrant-resistant HR+BC PDX model ST941, as described in the Examples below.
  • FIG. 4 is a panel showing three line graphs that depict changes in tumor volume (mm 3 ) over time (days) in PDX models of TNBC (BR5010; top), small cell lung cancer (LU5178; middle), and ovarian cancer (OV15398; bottom).
  • the animals were treated with Compound 101 as described in Example 10.
  • Data obtained from vehicle-treated (control) animals is represented by filled circles (upper traces in each graph).
  • Data from animals modeling TNBC and given 10 mg/kg Compound 101 QD are represented in the top graph by filled squares; the dose of 5 mg/kg BID is represented by triangles.
  • Triangles also represent data obtained from the animal models of SCLC and ovarian cancer treated with Compound 101 in the middle and bottom graphs.
  • FIG. 5 is a panel of line graphs showing tumor growth in the PDX models indicated and corresponding isobolograms, each generated as described in Example 11. Compound 101 was applied to cells in combination with the indicated second agents at the concentrations shown.
  • FIG. 7 is a Table summarizing the TGI values and genetic status of the 12 PDX models studied as described in Example 12. Models in the table are sorted based on highest to lowest response at end of study. BID, CNV, RB, SCLC, and TNBC are as defined for FIG. 6 and elsewhere herein.
  • tissue was not available for confirmation of RB pathway genetics.
  • a dose of about 10 mg means any dose as low as 10% less than 10 mg (9 mg), any dose as high as 10% more than 10 mg (11 mg), and any dose or dosage range therebetween (e.g., 9-11 mg; 9.1-10.9 mg; 9.2-10.8 mg; and so on).
  • a prevalence rank in a population of about 80% means a prevalence rank of 72-88% (e.g., 79.2-80.8%).
  • “about X” can be “X” (e.g., about 80% can be 80%). Where a stated value cannot be exceeded (e.g., 100%), “about” signifies any value or range of values that is up to and including 10% less than the stated value (e.g., a purity of about 100% means 90%-100% pure (e.g., 95%-100% pure, 96%-100% pure, 97%-100% pure etc. . . . )). In the event an instrument or technique measuring a value has a margin of error greater than 10%, a given value will be about the same as a stated value when they are both within the margin of error for that instrument or technique.
  • administering refers to the administration of a compound described herein (e.g., a compound of Formula (I), (Ia), a species thereof or a specified form thereof (e.g., a pharmaceutically acceptable salt of a compound of Formula (I), (Ia), or a species thereof), or an additional/second agent), or a composition containing the compound to a subject (e.g., a human patient) or system (e.g., a cell- or tissue-based system that is maintained ex vivo); as a result of the administration, the compound or composition containing the compound (e.g., a pharmaceutical composition) is introduced to the subject or system.
  • a compound described herein e.g., a compound of Formula (I), (Ia), a species thereof or a specified form thereof (e.g., a pharmaceutically acceptable salt of a compound of Formula (I), (Ia), or a species thereof), or an additional/second agent
  • a composition containing the compound to a subject or system.
  • compositions of the invention and second agents useful in combination therapies can also be “administered.”
  • routes of administration can be oral (i.e., by swallowing a pharmaceutical composition) or may be parenteral.
  • the route of administration can be bronchial (e.g., by bronchial instillation), by mouth (i.e., oral), dermal (which may be or comprise topical application to the dermis or intradermal, interdermal, or transdermal administration), intragastric or enteral (i.e., directly to the stomach or intestine, respectively), intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intratumoral, intravenous (or intra-arterial), intraventricular, by application to or injection into a specific organ (e.g., intrahepatic), mucosal (e.g., buccal, rectal, sublingual, or vaginal), subcutaneous, tracheal (e.g., by intratracheal instillation), or ocular (e.g., topical, subconjunctival, or intravitreal).
  • bronchial e.g., by bronchial instillation
  • mouth i.e., oral
  • Administration can involve intermittent dosing (i.e., doses separated by various times) and/or periodic dosing (i.e., doses separated by a common period of time (e.g., every so many hours, daily (e.g., once daily oral dosing), weekly, twice per week, etc.)). In other embodiments, administration may involve continuous dosing (e.g., perfusion) for a selected time (e.g., about 1-2 hours).
  • Two events, two entities, or an event and an entity are “associated” with one another if one or more features of the first (e.g., its presence, level and/or form) are correlated with a feature of the second.
  • a first entity e.g., an enzyme (e.g., CDK7)
  • gene expression profile i.e., a single or combined group of genes in a cell with a uniquely characteristic pattern of gene expression
  • metabolite, or event e.g., myeloid infiltration
  • an event e.g., the onset or progression of a particular disease
  • its presence, level and/or form correlates with the incidence of, severity of, and/or susceptibility to the disease (e.g., a cancer disclosed herein).
  • the biomarkers described herein are associated with an identified patient in the manner described herein (e.g., by virtue of their level of expression) and, depending on their status, can also be associated with a clinical outcome (e.g., a better prognosis based on an increased likelihood that a treatment regimen described herein will be more successful as evidenced by, e.g., TGI, preferably beyond the cessation of treatment). Associations are typically assessed across a relevant population. Two or more entities are physically “associated” with one another if they interact, directly or indirectly, so that they are and/or remain in physical proximity with one another in a given circumstance (e.g., within a cell maintained under physiological conditions (e.g., within cell culture) or within a pharmaceutical composition).
  • Entities that are physically associated with one another can be covalently linked to one another or non-covalently associated by, for example, hydrogen bonds, van der Waals forces, hydrophobic interactions, magnetism, or combinations thereof.
  • a compound of Formula (I), (Ia), a species thereof, or a specified form thereof (e.g., a pharmaceutically acceptable salt) can non-covalently associate with CDK7.
  • biological sample refers to a sample obtained or derived from a biological source of interest (e.g., a tissue or organism (e.g., an animal or human patient) or cell culture).
  • a biological sample can be a sample obtained from an individual (e.g., a patient or an animal model) suffering from a disease (or, in the case of an animal model, a simulation of that disease in a human patient) to be diagnosed and/or treated by the methods of this invention or from an individual serving in the capacity of a reference or control (or whose sample contributes to a reference standard or control population).
  • the biological sample can contain a biological cell, tissue or fluid or any combination thereof.
  • a biological sample can be or can include ascites; blood; blood cells; a bodily fluid, any of which may include or exclude cells (e.g., tumor cells (e.g., circulating tumor cells (CTCs) found in at least blood or lymph vessels)) or circulating tumor DNA (ctDNA); bone marrow or a component thereof (e.g., hematopoietic cells, marrow adipose tissue, or stromal cells); cerebrospinal fluid (CSF); feces; flexural fluid; free-floating nucleic acids (e.g., circulating tumor DNA); gynecological fluids; hair; immune infiltrates; lymph; peritoneal fluid; plasma; saliva; skin or a component part thereof (e.g., a hair follicle); sputum; surgically-obtained specimens; tissue scraped or swabbed from the skin or a mucus membrane (e.g., in the nose,
  • Samples of, or samples obtained from, a bodily fluid may include tumor cells (e.g., CTCs) and/or free-floating or cell-free nucleic acids of the tumor.
  • Cells e.g., cancer cells
  • Samples used in the form in which they were obtained may be referred to as “primary” samples, and samples that have been further manipulated (e.g., by removing one or more components of the sample) may be referred to as “secondary” or “processed” samples.
  • Such processed samples may contain or be enriched for a particular cell type (e.g., a CDK7-expressing cell, which may be a tumor cell), cellular component (e.g., a membrane fraction), or cellular material (e.g., one or more cellular proteins, including CDK7, DNA, or RNA (e.g., mRNA), which may encode CDK7 and may be subjected to amplification).
  • a CDK7-expressing cell which may be a tumor cell
  • cellular component e.g., a membrane fraction
  • cellular material e.g., one or more cellular proteins, including CDK7, DNA, or RNA (e.g., mRNA), which may encode CDK7 and may be subjected to amplification.
  • cellular material e.g., one or more cellular proteins, including CDK7, DNA, or RNA (e.g., mRNA), which may encode CDK7 and may be subjected to amplification.
  • biomarker refers to an entity whose state correlates with a particular biological event so that it is considered to be a “marker” for that event (e.g., the presence of a particular cancer and its susceptibility to a compound of Formula (I), (Ia), a species thereof, or a specified form thereof).
  • a biomarker can be analyzed at the nucleic acid or protein level; at the nucleic acid level, one can analyze the presence (e.g., copy number alterations (CNAs)), absence, or chromosomal location of a gene in wild type or mutant form, epigenetic alterations (in, e.g., methylation), its association with a super-enhancer, and/or its level of expression (as evidenced, for example, by primary RNA transcript or mRNA levels).
  • CNAs copy number alterations
  • a biomarker may indicate a therapeutic outcome or likelihood (e.g., increased likelihood) thereof.
  • a biomarker can be predictive or prognostic and is therefore useful in methods of identifying or treating a patient as described herein.
  • cancer refers to a disease in which biological cells exhibit an aberrant growth phenotype characterized by loss of control of cell proliferation to an extent that will be detrimental to a patient having the disease.
  • a cancer can be classified by the type of tissue in which it originated (histological type) and/or by the primary site in the body in which the cancer first developed. Based on histological type, cancers are generally grouped into six major categories: carcinomas; sarcomas; myelomas; leukemias; lymphomas; and mixed types.
  • a cancer treated as described herein may be of any one of these types and may comprise cells that are precancerous (e.g., benign), malignant, pre-metastatic, metastatic, and/or non-metastatic.
  • a patient who has a malignancy or malignant lesion has a cancer.
  • the present disclosure specifically identifies certain cancers to which its teachings may be particularly relevant, and one or more of these cancers may be characterized by a solid tumor or by a hematologic tumor, which may also be known as a blood cancer (e.g., of a type described herein).
  • a blood cancer e.g., of a type described herein.
  • cancer cell and “tumor cell” interchangeably to refer to any malignant cell.
  • combination therapy refers to those situations in which a subject is exposed to two or more therapeutic regimens (e.g., two or more therapeutic agents) to treat a single disease (e.g., a cancer).
  • the two or more regimens/agents may be administered simultaneously or sequentially.
  • a dose of the first agent and a dose of the second agent are administered at about the same time, such that both agents exert an effect on the patient at the same time or, if the first agent is faster- or slower-acting than the second agent, during an overlapping period of time.
  • the doses of the first and second agents are separated in time, such that they may or may not exert an effect on the patient at the same time.
  • the first and second agents may be given within the same hour or same day, in which case the first agent would likely still be active when the second is administered.
  • a much longer period of time may elapse between administration of the first and second agents, such that the first agent is no longer active when the second is administered (e.g., all doses of a first regimen are administered prior to administration of any dose(s) of a second regimen by the same or a different route of administration, as may occur in treating a refractory cancer).
  • combination therapy does not require that two agents be administered together in a single composition or at the same time, although in some embodiments, two or more agents, including a compound of Formula (I), (Ia), a species thereof, or a specified form thereof and a second agent described herein, may be administered within the same period of time (e.g., within the same hour, day, week, or month).
  • cutoff and “cutoff value” mean a value measured in an assay that defines the dividing line between two subsets of a population (e.g., likely responders and non-responders (e.g., responders and non-responders to a compound of Formula (I), (Ia), a species thereof, or a specified form thereof)).
  • values that are equal to or above the cutoff value define one subset of the population, and values that are lower than the cutoff value define the other subset of the population.
  • values that are equal to or below the cutoff value define on subset of the population, and values above the cutoff value define the other.
  • the cutoff or cutoff value can define the threshold value.
  • diagnosis information is information that is useful in determining whether a patient has a disease and/or in classifying (stratifying) the disease into a genotypic or phenotypic category or any category having significance with regard to the prognosis of the disease or its likely response to treatment (either treatment in general or any particular treatment described herein).
  • diagnostic refers to obtaining or providing any type of diagnostic information, including, but not limited to, whether a patient is likely to have or develop a disease; whether that disease has or is likely to reach a certain state or stage or to exhibit a particular characteristic (e.g., resistance to a therapeutic agent); information related to the nature or classification of a tumor; information related to prognosis (which may also concern resistance); and/or information useful in selecting an appropriate treatment (e.g., selecting a compound of Formula (I), (Ia), a species thereof, or a specified form thereof for a patient identified as having a cancer that is likely to respond to such an inhibitor or other treatment).
  • a particular characteristic e.g., resistance to a therapeutic agent
  • information related to the nature or classification of a tumor e.g., information related to prognosis (which may also concern resistance)
  • information useful in selecting an appropriate treatment e.g., selecting a compound of Formula (I), (Ia), a species thereof, or a specified form thereof for a patient identified
  • a patient classified (stratified) according to a method described herein and selected for treatment with a compound of Formula (I), (Ia), a species thereof, or a specified form thereof is likely to respond well to the treatment, meaning that such a patient is more likely to be successfully treated than a patient with the same type of cancer who has not been so identified and is not in the same strata.
  • Available treatments include therapeutic agents and other treatment modalities such as surgery, radiation, etc., and selecting an appropriate treatment encompasses the choice of withholding a particular therapeutic agent; the choice of a dosing regimen; and the choice of employing a combination therapy.
  • Diagnostic information can be used to stratify patients and is thus useful in identifying and classifying a given patient according to, for example, biomarker status. Obtaining diagnostic information can constitute a step in any of the patient stratification methods described herein.
  • dosage form may be used to refer to a physically discrete unit of an active agent (e.g., a therapeutic or diagnostic agent) for administration to a patient.
  • an active agent e.g., a therapeutic or diagnostic agent
  • each such unit contains a predetermined quantity of active agent.
  • such quantity is a unit dosage amount (or a whole fraction thereof) appropriate for administration in accordance with a dosing regimen that has been determined to correlate with a desired or beneficial outcome when administered to a relevant population (i.e., with a therapeutic dosing regimen).
  • the total amount of a therapeutic composition or agent administered to a particular patient is determined by one or more attending physicians and may involve administration of multiple dosage forms.
  • a dosing regimen may be used to refer to a set of unit doses (typically more than one) that are administered individually to a patient, separated by equal or unequal periods of time.
  • a given therapeutic agent typically has a recommended dosing regimen, which may involve one or more doses, each of which may contain the same unit dose amount or differing amounts.
  • a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount that is different from the first dose amount.
  • a dosing regimen is correlated with a desired or beneficial outcome when administered across a relevant population (i.e., the regimen is a therapeutic dosing regimen).
  • an “effective amount” of an agent refers to an amount that produces or is expected to produce the desired effect for which it is administered.
  • the effective amount will vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound administered, the condition being treated, the mode of administration, and characteristics of the patient, as discussed further below and recognized in the art.
  • the term can be applied to therapeutic and prophylactic methods.
  • a therapeutically effective amount is one that reduces the incidence and/or severity of one or more signs or symptoms of the disease.
  • an effective amount may reduce the tumor burden, stop tumor growth, inhibit metastasis or prolong patient survival.
  • a therapeutically effective amount is that amount that provides a particular desired pharmacological response in a significant number of patients when administered to patients in need of such treatment.
  • reference to a therapeutically effective amount may be a reference to an amount administered or an amount measured in one or more specific tissues (e.g., a tissue affected by the disease) or fluids (e.g., blood, saliva, serum, sweat, tears, urine, etc.).
  • Effective amounts may be formulated and/or administered in a single dose or in a plurality of doses, for example, as part of a dosing regimen.
  • an “enhancer” is a region of genomic DNA that helps regulate the expression of genes; enhancers have been found up to 1 Mbp away from a gene they regulate. An enhancer may overlap, but is often not composed of, gene coding regions. An enhancer is often bound by transcription factors and designated by specific histone marks.
  • patient refers to any organism that is or may be subjected to a diagnostic method described herein or to which a compound described herein, or a specified form thereof, is or may be administered for, e.g., experimental, diagnostic, prophylactic, and/or therapeutic purposes.
  • Typical patients include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans; domesticated animals, such as dogs and cats; and livestock or any other animal of agricultural or commercial value).
  • animals e.g., mammals such as mice, rats, rabbits, non-human primates, and humans; domesticated animals, such as dogs and cats; and livestock or any other animal of agricultural or commercial value).
  • a patient may be suffering from or susceptible to (i.e., have a higher than average risk of developing) a disease described herein and may display one or more signs or symptoms thereof.
  • composition when applied to a carrier used to formulate a composition disclosed herein (e.g., a pharmaceutical composition), means a carrier that is compatible with the other ingredients of the composition and not deleterious to a patient (e.g., it is non-toxic in the amount required and/or administered (e.g., in a unit dosage form)).
  • pharmaceutically acceptable when applied to a salt, solvate, stereoisomer, tautomer, or isotopic form of a compound described herein, refers to a salt, solvate, stereoisomer, tautomer, or isotopic form that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans (e.g., patients) and lower animals (including, but not limited to, mice and rats used in laboratory studies) without unacceptable toxicity, irritation, allergic response and the like, and that can be used in a manner commensurate with a reasonable benefit/risk ratio.
  • Many pharmaceutically acceptable salts are well known in the art (see, e.g., Berge et al., J. Pharm. Sci.
  • Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases.
  • suitable inorganic and organic acids and bases include those derived from suitable inorganic and organic acids and bases.
  • pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed 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 known in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, MALAT1e, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pec
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
  • the term “population” means some number of items (e.g., at least 30, 40, 50, or more) sufficient to reasonably reflect the distribution, in a larger group, of the value being measured in the population.
  • the population can be a discrete group of humans, laboratory animals, or cells lines (for example) that are identified by at least one common characteristic for the purposes of data collection and analysis.
  • a “population of samples” refers to a plurality of samples that is large enough to reasonably reflect the distribution of a value (e.g., a value related to the state of a biomarker) in a larger group of samples.
  • the items in the population may be biological samples, as described herein.
  • each sample in a population of samples may be cells of a cell line or a biological sample obtained from a patient or a xenograft (e.g., a tumor grown in a mouse by implanting a tumorigenic cell line or a patient sample into the mouse).
  • individuals within a population can be a discrete group identified by a common characteristic, which can be the same disease (e.g., the same type of cancer), whether the sample is obtained from living beings suffering from the same type of cancer or a cell line or xenograft representing that cancer.
  • prevalence cutoff means the prevalence rank that defines the dividing line between two subsets of a population (e.g., a subset of “responders” and a subset of “non-responders,” which, as the names imply include patients who are likely or unlikely, respectively, to experience a beneficial response to a therapeutic agent or agents).
  • a prevalence rank that is equal to or higher (e.g., a lower percentage value) than the prevalence cutoff defines one subset of the population; a prevalence rank that is lower (e.g., a higher percentage value) than the prevalence cutoff defines the other subset.
  • the term “prevalence rank” for a specified value means the percentage of a population that are equal to or greater than that specific value. For example, a 35% prevalence rank for the amount of mRNA of a specific biomarker in a test cell means that 35% of the population have that level of biomarker mRNA or greater than the test cell.
  • prognostic information and “predictive information” are used to refer to any diagnostic information that may be used to indicate any aspect of the course of a disease or condition either in the absence or presence of treatment. Such information may include, but is not limited to, the average life expectancy of a patient, the likelihood that a patient will survive for a given amount of time (e.g., 6 months, 1 year, 5 years, etc.), the likelihood that a patient will be cured of a disease, the likelihood that a patient's disease will respond to a particular therapy (wherein response may be defined in any of a variety of ways). Diagnostic information can be prognostic or predictive.
  • rank ordering means the ordering of values from highest to lowest or from lowest to highest.
  • RB-E2F pathway and “RB-E2F family” refer to a set of genes and the proteins encoded thereby, as the context will make clear, whose expression or activity regulates the activity of the RB gene family and in turn regulates the activity of the E2F family of transcription factors that are required for entry into and progression through the cell cycle.
  • the table below contains a list of genes in the RB-E2F family, an indication of a currently understood function of the encoded proteins and the status of these biomarkers in cancer.
  • a pre-determined threshold for such activated or overexpressed RB-E2F family members can be determined by comparative analysis and is a level (e.g., mRNA level, protein level, gene copy number, strength of enhancer associated with the gene) that, when found or exceeded in a cancer patient, identifies that patient as a candidate for treatment as described herein.
  • a pre-determined threshold for such inactivated or underexpressed RB-E2F family members can be determined by comparative analysis and is a level (e.g., mRNA level, protein level, CNV, strength of enhancer associated with the gene) that, when unattained in a cancer patient, identifies that patient as a candidate for treatment as described herein.
  • a “reference” refers to a standard or control relative to which a comparison is performed. For example, an agent, patient, population, sample, sequence, or value of interest is compared with a reference agent, patient, population, sample, sequence or value.
  • the reference can be analyzed or determined substantially simultaneously with the analysis or determination of the item of interest or it may constitute a historical standard or control, determined at an earlier point in time and optionally embodied in a tangible medium.
  • One of ordinary skill in the art is well trained in selecting appropriate references, which are typically determined or characterized under conditions that are comparable to those encountered by the item of interest.
  • One of ordinary skill in the art will appreciate when sufficient similarities are present to justify reliance on and/or comparison to a particular possible reference as a standard or control.
  • a “response” to treatment is any beneficial alteration in a patient's condition that results from, or that correlates with, treatment.
  • the alteration may be stabilization of the condition (e.g., inhibition of deterioration that would have taken place in the absence of the treatment), amelioration of, delay of onset of, and/or reduction in frequency of one or more signs or symptoms of the condition, improvement in the prospects for cure of the condition, greater survival time, and etc.
  • a response may be a patient's response or a tumor's response.
  • strength when used to refer to a portion of an enhancer or a SE, it means the area under the curve of the number of H3K27Ac or other genomic marker reads plotted against the length of the genomic DNA segment analyzed.
  • strength is an integration of the signal resulting from measuring the mark at a given base pair over the span of the base pairs defining the region being chosen to measure.
  • SE super-enhancer
  • SEs refers to a subset of enhancers that contain a disproportionate share of histone marks and/or transcriptional proteins relative to other enhancers in a particular cell or cell type. Genes regulated by SEs are predicted to be of high importance to the function of a cell. SEs are typically determined by rank ordering all of the enhancers in a cell based on strength and determining, using available software such as ROSE (bitbucket.org/young_computation/rose), the subset of enhancers that have significantly higher strength than the median enhancer in the cell (see, e.g., U.S. Pat. No. 9,181,580, which is hereby incorporated by reference herein in its entirety).
  • ROSE bitbucket.org/young_computation/rose
  • threshold and “threshold level” mean a level that defines the dividing line between two subsets of a population (e.g., responders and non-responders).
  • a threshold or threshold level can define a prevalence cutoff or a cutoff value.
  • treatment refers to reversing, alleviating, delaying the onset of, and/or inhibiting the progress of a “pathological condition” (e.g., a disease, such as cancer) described herein.
  • pathological condition e.g., a disease, such as cancer
  • “treatment,” “treat,” and “treating” require that signs or symptoms of the disease have developed or have been observed.
  • treatment may be administered in the absence of signs or symptoms of the disease or condition (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example, to delay or inhibit recurrence.
  • the terms “active agent,” “anti-cancer agent,” “pharmaceutical agent,” and “therapeutic agent” are used interchangeably (unless the context clearly indicates otherwise) and compounds of Formula (I), (Ia), a species thereof, or a specified form thereof, would be understood by one of ordinary skill in the art as active, anti-cancer, pharmaceutical, or therapeutic agents.
  • the treatment methods and uses encompass combination therapies/uses in which a compound of Formula (I), (Ia), a species thereof, or a specified form thereof is administered or used in combination with one or more additional agents (e.g., an additional anti-cancer therapeutic), as described herein.
  • additional agents e.g., an additional anti-cancer therapeutic
  • each therapeutic method and any diagnostic method that employs a compound of Formula (I), (Ia), a species thereof, or a specified form thereof may also be expressed in terms of use and vice versa.
  • the invention encompasses the use of a compound or composition described herein for the treatment of a disease described herein (e.g., cancer); a compound or composition for use in diagnosing and/or treating or a disease (e.g., cancer); and the use of the compound or composition for the preparation of a medicament for treating a disease described herein (e.g., cancer).
  • a patient subjected to a diagnostic or therapeutic method described herein may have a blood cancer, which may also be referred to as a hematopoietic or hematological cancer or malignancy, and any of the methods described herein can entail analyzing a biomarker described herein in a biological sample of, e.g., blood or lymph, obtained from the patient.
  • a blood cancer which may also be referred to as a hematopoietic or hematological cancer or malignancy
  • any of the methods described herein can entail analyzing a biomarker described herein in a biological sample of, e.g., blood or lymph, obtained from the patient.
  • the blood cancer can be a leukemia such as acute lymphocytic leukemia (ALL; e.g., B cell ALL or T cell ALL), acute myelocytic leukemia (AML; e.g., B cell AML or T cell AML), chronic myelocytic leukemia (CML; e.g., B cell CML or T cell CML), chronic lymphocytic leukemia (CLL; e.g., B cell CLL (e.g., hairy cell leukemia) or T cell CLL), chronic neutrophilic leukemia (CNL), or chronic myelomonocytic leukemia (CMML).
  • ALL acute lymphocytic leukemia
  • AML acute myelocytic leukemia
  • CML chronic myelocytic leukemia
  • CLL chronic lymphocytic leukemia
  • CLL chronic lymphocytic leukemia
  • CLL chronic neutrophilic leukemia
  • CML chronic myelomonoc
  • the blood cancer can also be a lymphoma such as Hodgkin lymphoma (HL; e.g., B cell HL or T cell HL), non-Hodgkin lymphoma (NHL, which can be deemed aggressive; e.g., B cell NHL or T cell NHL), follicular lymphoma (FL), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), a marginal zone lymphoma (MZL), such as a B cell lymphoma (e.g., splenic marginal zone B cell lymphoma), primary mediastinal B cell lymphoma (e.g., splenic marginal zone B cell lymphoma), primary mediastinal B cell lymphoma, Burkitt lymphoma (BL), lymphoplasmacytic lymphoma (i.e., Waldenstrom's macroglobulinemia), immunoblastic large cell lymphom
  • the B cell NHL can be diffuse large cell lymphoma (DLCL; e.g., diffuse large B cell lymphoma (DLBCL; e.g., germinal center B cell-like (GCB) DLBCL or activated B-cell like (ABC) DLBCL)), and the T cell NHL can be precursor T lymphoblastic lymphoma or a peripheral T cell lymphoma (PTCL).
  • DLCL diffuse large cell lymphoma
  • DLBCL diffuse large B cell lymphoma
  • GCB germinal center B cell-like
  • ABSC activated B-cell like
  • the PTCL can be a cutaneous T cell lymphoma (CTCL) such as mycosis fungoides or Sezary syndrome, angioimmunoblastic T cell lymphoma, extranodal natural killer T cell lymphoma, enteropathy type T cell lymphoma, subcutaneous anniculitis-like T cell lymphoma, or anaplastic large cell lymphoma.
  • CCL cutaneous T cell lymphoma
  • the cancer is characterized by a solid tumor considered to be either of its primary location or metastatic.
  • the cancer or tumor treated or prevented as described herein is an acoustic neuroma; adenocarcinoma; adrenal gland cancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangio-endotheliosarcoma, hemangiosarcoma); appendix cancer; benign monoclonal gammopathy (also known as monoclonal gammopathy of unknown significance (MGUS); biliary cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast; any of which may be present in subjects having a particular profile, such as an HR+(ER+ or PR+), HER2+, HR ⁇ (having neither estrogen nor pro
  • liver cancer e.g., hepatocellular cancer (HCC), malignant hepatoma
  • lung cancer e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma, squamous cell carcinoma, or large cell carcinoma of the lung
  • leiomyosarcoma LMS
  • mastocytosis e.g., systemic mastocytosis
  • mouth cancer muscle cancer
  • myelodys-plastic syndrome MDS
  • mesothelioma myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a.
  • MMD myeloproliferative disorder
  • MPD e.g., polycythemia vera (PV), essential thrombocytosis (ET), agnogenic myeloid
  • myelofibrosis MF
  • chronic idiopathic myelofibrosis hypereosinophilic syndrome (HES)
  • neuroblastoma e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis
  • neuroendocrine cancer e.g., gastroentero-pancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor
  • osteosarcoma e.g., bone cancer
  • ovarian cancer e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma, HGSOC, LGSOC, epithelial ovarian cancer (e.g., ovarian clear cell carcinoma or mucinous carcinoa), sex cord stromal tumors (granulosa cell), and endometroid tumors); papillary adenocarcinoma; pancreatic cancer (whether an exocrine tumor (e.g.
  • GI tract cancer refers to a cancer present anywhere in the GI tract, including cancers of the mouth, throat, esophagus, stomach, large or small intestine, rectum, and anus.
  • the cancer can be a neuroendocrine cancer, and such tumors can be treated as described herein regardless of the organ in which they present.
  • a biomarker described herein can be analyzed in a biological sample containing tumor cells or ctDNA of any of the cancer types just listed.
  • a patient identified by analyzing a biomarker as described herein can be “newly diagnosed” and therefor previously unexposed to a compound of Formula (I), (Ia), a species thereof, or a specified form thereof and, similarly, previously unexposed to a second agent as described herein.
  • the methods of the invention may specifically exclude any one or more of the types of cancers described herein.
  • the invention features methods of treating cancer by administering a compound of Formula (I), (Ia), a species thereof, or a specified form thereof, with the proviso that the cancer is not a breast cancer; with the proviso that the cancer is not a breast cancer or a leukemia; with the proviso that the cancer is not a breast cancer, a leukemia, or an ovarian cancer; and so forth, with exclusions selected from any of the cancers listed herein and with the same notion of variable exclusion from lists of elements relevant to other aspects of the invention (e.g., chemical substituents of a compound described herein or components of kits and pharmaceutical compositions).
  • elements are presented as lists (e.g., in Markush group format), every possible subgroup of the elements is also disclosed, and any element(s) can be removed from
  • the invention features the use of a compound of Formula (I), (Ia), a species thereof, or a specified form thereof in treating cancer in a patient who has been identified by analyzing the biomarker BCL2, RB1, RBL1, RBL2, CDKN2A, CDKN2B, CDKN2C, CDKN2D, CDKN1A, CDKN1B, CDKN1C, or FBXW7 in a biological sample containing cancer cells or ctDNA from the patient.
  • Analyzing the biomarker can include analyzing its sequence to detect a mutation or determining CNA, association with a SE, RNA expression level (e.g., mRNA expression) or another feature described above as indicating the state of the biomarker.
  • a patient identified by analyzing BCL2, RB1, RBL1, RBL2, CDKN2A, CDKN2B, CDKN2C, CDKN2D, CDKN1A, CDKN1B, CDKN1C, or FBXW7 can be: treated with a platinum-based therapeutic agent (e.g., carboplatin, cisplatin, or oxaliplatin) as a second agent; a patient whose cancer has developed resistance to a platinum-based therapeutic agent (e.g., carboplatin, cisplatin, or oxaliplatin); or a patient undergoing treatment with a CDK4/6 inhibitor used alone or in combination with one or more of an aromatase inhibitor, a selective estrogen receptor modulator (SERM), selective estrogen receptor degrader (SERD), or estrogen suppressant, any of which may be selected from the descriptions of such agents provided herein or known in the art.
  • a platinum-based therapeutic agent e.g., carboplatin, cis
  • the cancer can be a breast cancer (e.g., a triple negative breast cancer (TNBC), HR+, or other type of breast cancer described herein), an ovarian cancer (e.g., HGSOC), a lung cancer (e.g., SCLC, NSCLC or other lung cancer described herein), retinoblastoma, or a blood cancer (e.g., acute myeloid leukemia (AML)).
  • TNBC triple negative breast cancer
  • HR+ or other type of breast cancer described herein
  • an ovarian cancer e.g., HGSOC
  • a lung cancer e.g., SCLC, NSCLC or other lung cancer described herein
  • retinoblastoma e.g., acute myeloid leukemia (AML)
  • AML acute myeloid leukemia
  • the methods of treating such a patient include a step of administering an effective amount of a compound of Formula (I), (Ia), a species thereof or a specified form thereof, optionally within a pharma-ceutical composition described herein and/or according to a dosing regimen described herein.
  • the invention features the use of a compound of Formula (I), (Ia), a species thereof, or a specified form thereof in treating cancer in a patient who has been identified by analyzing the biomarker CCNE1, CCNE2, RB1, CDK6, CCND1, CCND2, CCND3, or CCKN2A in a biological sample containing cancer cells or ctDNA from the patient.
  • Analyzing the biomarker can include analyzing its sequence to detect a mutation or determining CNA, association with a SE, RNA expression level (e.g., mRNA expression) or another feature described above as indicating the state of the biomarker.
  • a patient identified by analyzing CCNE1, CCNE2, RB1, CDK6, CCND1, CCND2, CCND3, or CCKN2A can be a patient who has undergone, is presently undergoing, or who will undergo (e.g., has been prescribed) treatment with a Bcl-2 inhibitor, such as venetoclax, a SERM, such as tamoxifen, a SERD, such as fulvestrant, or a PARP inhibitor, such as olaparib or niraparib.
  • a Bcl-2 inhibitor such as venetoclax
  • SERM such as tamoxifen
  • SERD such as fulvestrant
  • PARP inhibitor such as olaparib or niraparib.
  • the patient may have a breast cancer (e.g., TNBC or an HR+ breast cancer), lymphoma, melanoma (e.g., familial melanoma), ovarian cancer (e.g., HGSOC), or pancreatic cancer (e.g., PDAC).
  • a breast cancer e.g., TNBC or an HR+ breast cancer
  • lymphoma e.g., melanoma (e.g., familial melanoma), ovarian cancer (e.g., HGSOC), or pancreatic cancer (e.g., PDAC).
  • the biomarker is CDKN2A
  • the patient may have TNBC, PDAC, or HGSOC.
  • the biomarker is CCNE1
  • the patient may have TNBC, HGSOC, melanoma (e.g., familial melanoma), or lymphoma.
  • the biomarker BCL2 encompasses analysis of the biomarker gene BCL2-like 1 and the biomarker protein (BCL2) encoded thereby
  • the biomarker CCNE1 encompasses analysis of the biomarker gene CCNE1 and the biomarker protein (cyclin E1) encoded thereby; and so forth.
  • the methods of treating such a patient include a step of administering an effective amount of a compound of Formula (I), (Ia), a species thereof or a specified form thereof, optionally within a pharmaceutical composition described herein and/or according to a dosing regimen described herein.
  • the invention features the use of a compound of Formula (I), (Ia), a species thereof, or a specified form thereof in treating cancer in a patient who has been identified by analyzing the biomarker MYC (see Kalkat et al., Genes 8(6):151, 2017), CDK1, CDK2, CDK4, CDK17, CDK18, CDK19, CCNA1, CCNB1, ESR-1 or FGFR1 in a biological sample containing cancer cells or ctDNA from the patient.
  • Analyzing the biomarker can include analyzing any mutations within MYC, CDK1, CDK2, CDK4, CDK17, CDK18, CDK19, CCNA1, CCNB1, ESR-1 or FGFR1 or determining CNA, association with a SE, RNA expression level (e.g., mRNA expression) or another feature described above as indicating the state of the biomarker.
  • RNA expression level e.g., mRNA expression
  • the patient may have a breast cancer (e.g., TNBC or an ovarian cancer (e.g., HGSOC) and may be resistant to a platinum-based anti-cancer agent, such as carboplatin, cisplatin, or oxaliplatin, resistant to gemcitabine, resistant to a PARP inhibitor, such as olaparib or niraparib, or resistant to a taxane, such as paclitaxel.
  • the methods of treating such a patient include a step of administering an effective amount of a compound of Formula (I), (Ia), a species thereof or a specified form thereof, optionally within a pharmaceutical composition described herein and/or according to a dosing regimen described herein.
  • C-myc encodes at least two phosphoproteins with apparent molecular weights of 62,000 and 66,000 (see Ramsay et al., Proc. Natl. Acad. Sci . ( USA ) 81(24):7742-7746, 1984), and it has been determined through H3K27Ac ChIP-seq (ChIP-sequencing) methods that there is a SE locus associated with the MYC gene at chr8:128628088-128778308 (Gencode v19 annotation of the human genome build hg19/GRCh37).
  • the invention features the use of a compound of Formula (I), (Ia), a species thereof, or a specified form thereof in treating cancer in a patient who has been identified by analyzing the biomarker CDK7 or CDK9.
  • Analyzing the biomarker can include analyzing any mutations within CDK7 or CDK9 or determining CNA, association with a SE, RNA expression level (e.g., mRNA expression) or another feature described above as indicating the state of the biomarker.
  • the patient may have a lymphoma and the diagnosing/identifying step may more specifically be based on analysis of CDK7 (e.g., the level of CDK7 mRNA); the patient may have a breast cancer (e.g., TNBC), with the diagnosing/identifying step more specifically based on CDK9 (e.g., the level of CDK9 mRNA); the patient may have a TNBC or a lung cancer (e.g., SCLC), with the diagnosing step more specifically be based CDK19 (e.g., on the level of CDK19 mRNA).
  • CDK7 e.g., the level of CDK7 mRNA
  • the patient may have a breast cancer (e.g., TNBC), with the diagnosing/identifying step more specifically based on CDK9 (e.g., the level of CDK9 mRNA); the patient may have a TNBC or a lung cancer (e.g., SCLC), with the diagnosing step more specifically be based CDK19 (e.g
  • the methods of treating such a patient include a step of administering an effective amount of a compound of Formula (I), (Ia), a species thereof or a specified form thereof, optionally within a pharmaceutical composition described herein and/or according to a dosing regimen described herein.
  • the invention features the use of a compound of Formula (I), (Ia), a species thereof, or a specified form thereof in treating cancer in a patient who has been identified by analyzing the biomarker BRAF, E2F1, E2F2, E2F3, E2F4, E2F5, E2F6, E2F7, or E2F8 in a biological sample containing cancer cells or ctDNA from the patient.
  • Analyzing the biomarker can include analyzing its sequence to detect a mutation or determining CNA, association with a SE, RNA expression level (e.g., mRNA expression) or another feature described above as indicating the state of the biomarker.
  • a patient identified by analyzing BRAF, E2F1, E2F2, E2F3, E2F4, E2F5, E2F6, E2F7, or E2F8 can be a patient who has undergone, is presently undergoing, or who will undergo (e.g., has been prescribed) treatment with a PI3K inhibitor, such as alpelisib or capecitabine, a platinum-based anti-cancer agent, such as carboplatin, cisplatin, or oxaliplatin, or vincristine.
  • a PI3K inhibitor such as alpelisib or capecitabine
  • a platinum-based anti-cancer agent such as carboplatin, cisplatin, or oxaliplatin, or vincristine.
  • the patient may have a melanoma, lung cancer (e.g., NSCLC), GI tract cancer (e.g., CRC), thyroid cancer, retinoblastoma, or leukemia (e.g., hairy cell leukemia).
  • the methods of treating such a patient include a step of administering an effective amount of a compound of Formula (I), (Ia), a species thereof or a specified form thereof, optionally within a pharmaceutical composition described herein and/or according to a dosing regimen described herein.
  • a compound or other composition described herein e.g., a pharmaceutical composition comprising a compound of Formula (I), (Ia), a species thereof or specified form thereof
  • a combination therapy e.g., as defined and further described herein
  • a second agent described herein or a plurality thereof i.e., a patient identified as described herein may be treated with first, second, and third agents.
  • the additional/second agent employed in a combination therapy is most likely to achieve a desired effect for the same disorder (e.g., the same cancer), however it may achieve different effects that aid the patient.
  • the invention features pharmaceutical compositions containing a compound of Formula (I), (Ia), a species thereof, or a specified form thereof (e.g., a pharmaceutically acceptable salt), optionally in a therapeutically effect amount, for use in treating a patient identified as described herein.
  • the pharmaceutical compositions may optionally include any of the additional/second agents described herein and will include a pharmaceutically acceptable carrier.
  • the second/additional agent can be selected from a Bcl-2 inhibitor such as venetoclax, a PARP inhibitor such as olaparib or niraparib, a platinum-based anti-cancer agent such as carboplatin, cisplatin, or oxaliplatin, a taxane such as docetaxel or paclitaxel (or paclitaxel protein-bound (available as Abraxane®)), a CDK4/6 inhibitor such as palbociclib, ribociclib, abemaciclib, or trilaciclib, a selective estrogen receptor modulator (SERM) such as tamoxifen (available under the brand names NolvadexTM and SoltamoxTM), raloxifene (available under the brand name EvistaTM), and toremifene (available as FarestonTM) and a selective estrogen receptor degrader such as fulvestrant (available as FaslodexTM), each in a therapeutically effective amount.
  • the second therapeutic agent when employing a combination of a compound of Formula (I), (Ia), a species thereof, or a specified variant thereof and a second therapeutic agent in a method of the invention, can be administered concurrently with, prior to, or subsequent to a compound of Formula (I), (Ia), a species thereof, or a specified form thereof.
  • the second therapeutic pharmaceutical agent may be administered at a dose and/or on a time schedule determined for that pharmaceutical agent.
  • An additional/second therapeutic agent may also be administered together with the compound of Formula (I), (Ia), a species thereof, or a specified form thereof in a single dosage form or administered separately in different dosage forms.
  • the second therapeutic agents utilized in combination with a compound of Formula (I), (Ia), a species thereof, or a specified form thereof will be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels of the second therapeutic agent utilized in combination will be lower than those utilized in a monotherapy due to synergistic effects.
  • the cancer is TNBC, an ER+ breast cancer, pancreatic cancer (e.g., PDAC), or a squamous cell cancer of the head or neck and the second agent is a CDK4/6 inhibitor;
  • the cancer is a breast cancer (e.g., TNBC) or an ovarian cancer and the second agent is a PARP inhibitor;
  • the cancer is a leukemia (e.g., AML) and the second agent is a FLT3 inhibitor;
  • the cancer is an ovarian cancer (e.g., HGSOC) and the second agent is a platinum-based anti-cancer agent;
  • the cancer is a breast cancer (e.g., TNBC), a leukemia (e.g., AML), Ewing's sarcoma, or an osteosarcoma and the second agent is a BET inhibitor;
  • the cancer is a breast cancer (e.g., TNBC), a leukemia (e.g., AML), Ewing's s
  • the cancer is AML and the second agent is a Bcl-2 inhibitor, such as venetoclax;
  • the cancer is an epithelial ovarian cancer, a fallopian tube cancer, a primary peritoneal cancer, a triple negative breast cancer or a Her2 + /ER ⁇ /PR ⁇ breast cancer and the second agent is a PARP inhibitor, such as olaparib or niraparib;
  • the cancer is an ovarian cancer and the second agent is a platinum-based anti-cancer agent, such as carboplatin, cisplatin, or oxaliplatin.
  • a method of treatment can either be carried out on an identified patient without an explicit step of analyzing the biomarker or with an explicit step in which the biomarker is analyzed (e.g., by obtaining a biological sample from a patient).
  • a patient identified as described herein can be treated with a combination of a compound of Formula (I), (Ia), a species thereof, or a specified form thereof and one or more of a second agent that can be, but is not limited to, a Bcl-2 inhibitor such as APG-1252, APG-2575, BP1002 (prexigebersen), the antisense oligonucleotide known as oblimersen (G3139), S55746/BCL201, or venetoclax (e.g., venetoclax tablets marketed as Venclexta®); a CDK9 inhibitor such as alvocidib/DSP-2033/flavopiridol, AT7519, AZD5576, BAY1251152, BAY1143572, CYC065, nanoflavopiridol, NVP2, seliciclib (CYC202), TG02, TP-1287, VS2-370 or voruciclib (formerly P1446A-05);
  • a platinum-based therapeutic agent such as cisplatin, oxaliplatin (e.g., marketed as Eloxatin®), nedaplatin, carboplatin (e.g., marketed as Paraplatin®), phenanthriplatin, picoplatin, satraplatin (JM216), or triplatin tetranitrate; a CDK4/6 inhibitor such as BPI-1178, G1T38, palbociclib (e.g., marketed as Ibrance®), ribociclib (e.g., marketed as Kisqali®), ON 123300, trilaciclib, or abemaciclib (e.g., marketed as Verzenio®); a MEK inhibitor such as trametinib (e.g., marketed as Mekinist®), cobimetinib
  • the PI3K inhibitor can be apitolisib (GDC-0980), idelalisib (e.g., marketed as Zydelig®), copanlisib (e.g., marketed as Aliqopa®), duvelisib (e.g., marketed as Copiktra®), pictilisib (GDC-0941), or alpelisib (e.g., marketed as Piqray®).
  • the additional/second agent can be capecitabine (e.g., marketed as Xeloda®).
  • Such PI3K inhibitors can be combined with a compound of Formula (I), (Ia), a species thereof or specified form thereof in treating, e.g., HR+ breast cancer, TNBC, lymphoma (e.g., follicular lymphoma or non-Hodgkin lymphoma), or leukemia (e.g., CLL).
  • the additional/second agent can be gemcitabine (combined with a compound of the invention to treat, e.g., TNBC, CRC, SCLC, or a pancreatic cancer (e.g., PDAC)).
  • the additional/second agent can be an antimetabolite, such as the pyrimidine analog 5-fluorouracil (5-FU), which may be used in combination with a compound of Formula (I), (Ia), a species thereof, or a specified form thereof, and one or more of leucovorin, methotrexate, or oxaliplatin.
  • the additional/second agent can be an aromatase inhibitor, such as exemestane or anastrasole.
  • the additional/second agent is an inhibitor of the PI3K/AKT/mTOR pathway (e.g., gedatolisib).
  • the methods encompass the use of or administration of a compound of Formula (I), (Ia), a species thereof or a specified form thereof, to a patient identified as described herein, in combination with a MEK inhibitor, such as trametinib (available as Mekinist®), cobimetinib (available as Cotellic®), or binimetinib (available as Braftovi®)
  • a MEK inhibitor such as trametinib (available as Mekinist®), cobimetinib (available as Cotellic®), or binimetinib (available as Braftovi®)
  • APG-1252 is a dual Bcl-2/Bcl-xL inhibitor that has shown promise in early clinical trials when patients having SCLC or another solid tumor were dosed between 10-400 mg (e.g., 160 mg) intravenously twice weekly for three weeks in a 28-day cycle (see Lakhani et al., J. Clin. Oncol. 36:15_suppl, 2594, and ClinicalTrials.gov identifier NCT03080311).
  • APG-2575 is a Bcl-2 selective inhibitor that has shown promise in preclinical studies of FL and DLBCL in combination with ibrutinib (see Fang et al., AACR Annual Meeting 2019 , Cancer Res. 79(13 Suppl):Abstract No.
  • BP1002 is an uncharged P-ethoxy antisense oligodeoxynucleotide targeted against Bcl-2 mRNA that may have fewer adverse effects than other antisense analogs and has shown promise in inhibiting the growth of human lymphoma cell lines inclubated with BP1002 for four days and of CJ cells (transformed FL cells) implanted into SCID mice (see Ashizawa et al., AACR Annual Meeting 2017 , Cancer Res. 77(13 Suppl):Abstract No. 5091). BP1002 has also been administered in combination with cytarabine (LDAC) to patients having AML (see ClinicalTrials.gov identifier NCT04072458).
  • LDAC cytarabine
  • S55746/BCL201 is an orally available, selective Bcl-2 inhibitor that, in mice, demonstrated anti-tumor efficacy in two blood cancer xenograft models (Casara et al., Oncotarget 9(28):20075-88, 2018).
  • a phase I dose-escalation study was designed to administer film-coated tablets containing 50 or 100 mg of S55746, in doses up to 1500 mg, to patients with CLL or a B cell NHL including FL, MCL, DLBCL, SLL, MZL, and MM (see ClinicalTrials.gov identifier NCT02920697).
  • Venetoclax tablets have been approved for treating adult patients with CLL or SLL and, in combination with azacytidine, or decitabine, or low-dose cytarabine, for treating newly-diagnosed AML in patients who are at least 75 years old or who have comorbidities that preclude the use of intensive induction chemotherapy.
  • Dosing for CLL/SLL can follow the five-week ramp-up schedule and dosing for AML can follow the four-day ramp-up, both described in the product insert, together with other pertinent information (see also U.S. Pat. Nos. 8,546,399; 9,174,982; and 9,539,251, which are hereby incorporated by reference in their entireties).
  • BAY1251152 was the subject of a phase I clinical trial to characterize the MTD in patients with advanced blood cancers; the agent was infused weekly in 21-day cycles (see ClinicalTrials.gov identifier NCT02745743; see also Luecking et al., AACR 2017 Abstract No. 984).
  • Voruciclib is a clinical stage oral CDK9 inhibitor that represses MCL-1 and sensitizes high-risk DLBCL to BCL2 inhibition.
  • Dey et al. ( Scientific Reports 7:18007, 2017) suggest that the combination of voruciclib and venetoclax is promising for a subset of high-risk DLBCL patients (see also ClinicalTrials.gov identifier NCT03547115).
  • Fulvestrant has been approved for administration to postmenopausal women with advanced hormone receptor (HR)-positive, HER2-negative breast cancer, with HR-positive metastatic breast cancer whose disease progressed after treatment with other anti-estrogen therapies, and in combination with palbociclib (Ibrance®). Fulvestrant is administered by intramuscular injection at 500 or 250 mg (the lower dose being recommended for patients with moderate hepatic impairment) on days 1, 15, and 29, and once monthly thereafter (see the product insert for additional information; see also U.S. Pat. Nos. 6,744,122; 7,456,160; 8,329,680; and 8,466,139, each of which are hereby incorporated by reference herein in their entireties).
  • HR advanced hormone receptor
  • HER2-negative breast cancer with HR-positive metastatic breast cancer whose disease progressed after treatment with other anti-estrogen therapies, and in combination with palbociclib (Ibrance®).
  • Fulvestrant is administered by intramuscular injection at 500 or 250 mg (the lower dose being recommended for patients with moderate
  • Ponatinib has been administered in clinical trials to patients with CML or ALL (see ClinicalTrials.gov identifiers NCT0066092072, NCT012074401973, NCT02467270, NCT03709017, NCT02448095, NCT03678454, and NCT02398825) as well as solid tumors, such as biliary cancer and NSCLC (NCT02265341, NCT02272998, NCT01813734, NCT02265341, NCT02272998, NCT01813734, NCT02265341, NCT02272998, NCT01813734, NCT01935336, NCT03171389, and NCT03704688; see also the review article by Tan et al., Onco.
  • Alpelisib is a kinase inhibitor indicated in combination with fulvestrant for the treatment of postmenopausal women, and men, with HR+/HER2 ⁇ /PIK3CA-mutated, advanced or metastatic breast cancer as deteted by an FDA-approved test following progression on or after an endocrine-based regimen.
  • the recommended dose is 300 mg (two 150 mg tablets) taken orally once daily with food, which, as for all chemotherapeutic agents, may be interrupted, reduced, or discontinued to manage adverse reactions.
  • Paclitaxel is supplied as a nonaqueous solution intended for dilution with a suitable parenteral fluid prior to intravenous infusion.
  • Taxol® Under the brand name Taxol®, it is supplied in 30 mg, 100 mg, and 300 mg vials and can be used in a combination therapy described herein to treat a variety of cancers, including those of the bladder, breast, esophagus, fallopian tube or ovary, lung, skin (melanoma), and prostate.
  • Palbociclib has been approved for use in HR+/HER2 ⁇ advanced or metastatic breast cancer at a recommended dose of 125 mg daily, by mouth.
  • the invention can be used to treat a patient as identified herein with a compound of Formula (I), (Ia), a species thereof, or a specified form thereof, either alone or in combination with an aromatase inhibitor or fulvestrant.
  • a compound of Formula (I), (Ia), a species thereof, or a specified form thereof either alone or in combination with an aromatase inhibitor or fulvestrant.
  • the information provided here and publicly available can be used to practice the methods and uses of the invention.
  • the invention encompasses combination therapies that require a compound of the invention or a specified form thereof and any one or more additional/second agents, which may be administered at or below a dosage currently approved for single use (e.g., as described above), to a patient as described herein.
  • Triplet combinations include a compound of Formula (I), (Ia), a species thereof, or a specified form thereof with: alpelisib and fulvestrant or alpelisib and a taxane (for, e.g., treating NSCLC).
  • the patient can have a breast cancer (e.g., TNBC or an ER+ breast cancer), pancreatic cancer, lung cancer (e.g., SCLC or NSCLC), or squamous cell cancer of the head and neck;
  • a CDK9 inhibitor the patient can have a breast cancer and, more specifically, a Her2 + /ER ⁇ /PR ⁇ breast cancer;
  • a Flt3 inhibitor e.g., midostaurin
  • the patient can have a hematological cancer (e.g., AML);
  • a BET inhibitor the patient can have a hematological cancer (e.g., AML), a breast cancer (e.g., TNBC), an osteosarcoma or Ewing's Sarcoma;
  • a Bcl-2 inhibitor e.g., venetoclax
  • the patient can have a breast cancer (e.g., TNBC), an ovarian cancer, a lung cancer
  • the invention provides a method of treating a patient having a cancer and identified as described herein, which comprises administering to a patient identified as having either (a) a level of CCNE1 mRNA or protein in the cancer equal to or above a pre-determined threshold; and/or (b) a level of RB1 mRNA or protein in the cancer equal to or below a pre-determined threshold, an effective amount of a CDK7 inhibitor of Formula (I).
  • the method further comprises determining a level of RB1 and/or CCNE1 mRNA or protein present in a sample of cancer cells from the patient.
  • the human patient is diagnosed as having a cancer sensitive to a CDK7 inhibitor responsive to the determination; is suffering from ovarian cancer; or is suffering from a breast cancer (e.g., TNBC or an HR + breast cancer).
  • a compound of Formula (I), (Ia), a species thereof or a specified form thereof is co-administered with a PARP inhibitor.
  • the compound of Formula (I), (Ia), a species thereof or a specified form thereof is co-administered with a SERM (e.g., tamoxifen, raloxifene, or toremifene), a SERD such fulvestrant, or an agent that inhibits the production of estrogen (e.g., an aromatase inhibitor such as anastrozole (available as Arimidex®), exemestane (available as Aromasin®), and letrozole (available as Femara®), optionally to treat a cancer that is refractory to palbociclib.
  • a SERM e.g., tamoxifen, raloxifene, or toremifene
  • a SERD such fulvestrant
  • an agent that inhibits the production of estrogen e.g., an aromatase inhibitor such as anastrozole (available as Arimidex®), exemestane (available as Aromasin®), and letroz
  • the invention provides methods of treating cancer in a patient identified as described herein by administering to the patient a combination of a compound of Formula (I), (Ia), a species thereof, or a specified form thereof and a platinum-based standard of care (SOC) anti-cancer agent for such cancer or a taxane.
  • the cancer can be an ovarian cancer and the SOC anti-cancer agent can be a platinum-based anti-cancer agent (e.g., carboplatin, cisplatin, or oxaliplatin).
  • the human patient is, has been determined to be, or has become resistant (after some initial responsiveness) to the platinum-based anti-cancer agent when administered as either a monotherapy or in combination with an anti-cancer agent other than a CDK7 inhibitor. In some aspects of this embodiment, the human patient is determined to have become resistant to the platinum-based anti-cancer agent when administered as a monotherapy or in combination with an anti-cancer agent other than a CDK7 inhibitor after some initial efficacy of that prior treatment. In some aspects of this embodiment, the SOC anti-cancer agent is a taxane (e.g., paclitaxel).
  • the invention also provides methods of treating a biomarker-identified HR + breast cancer in a human patient selected on the basis of being resistant to treatment with a CDK4/6 inhibitor comprising the step of administering to the patient a compound of Formula (I), (Ia), a species thereof, or a specified form thereof.
  • the patient prior to administration of the compound of Formula (I), (Ia), a species thereof, or a specified form thereof, the patient is, has been determined to be, or has become resistant (after some initial responsiveness) to a prior treatment with a CDK4/6 inhibitor alone or in combination with another SOC agent for breast cancer other than a CDK7 inhibitor, such as an aromatase inhibitor (e.g., letrozole, anastrozole) or a SERM (e.g., tamoxifen, raloxifene, or toremifene), SERD (e.g., fulvestrant), or estrogen suppressant such as anastrozole (available as Arimidex®), exemestane (available as Aromasin®), or letrozole (available as Femara®).
  • an aromatase inhibitor e.g., letrozole, anastrozole
  • SERM e.g., tamoxifen, raloxifene, or toremifen
  • the identified patient is selected for treatment with a compound of Formula (I), (Ia), a species thereof, or a specified form thereof on the basis of being resistant to prior treatment with a CDK4/6 inhibitor alone or in combination with another SOC agent for breast cancer other than a CDK7 inhibitor.
  • the compound of Formula (I), (Ia), a species thereof, or a specified form thereof is co-administered with another SOC agent, such as an aromatase inhibitor (e.g. anastrozole, exemestane, or letrozole) and/or a SERM or SERD, e.g., as described herein, or a second line treatment after failure on an aromatase inhibitor or fulvestrant.
  • another SOC agent such as an aromatase inhibitor (e.g. anastrozole, exemestane, or letrozole) and/or a SERM or SERD, e.g., as described herein, or a second line treatment after failure on an aroma
  • the patient prior to administration of the compound of Formula (I), (Ia), a species thereof, or a specified form thereof, the patient is, has been determined to be, or has become resistant (after some initial responsiveness) to treatment with a CDK4/6 inhibitor alone or in combination with another SOC agent for breast cancer other than a CDK7 inhibitor, such as an aromatase inhibitor (e.g., anastrozole, exemestane, or letrozole), or a SERM or SERD such as tamoxifen or fulvestrant; and the compound of Formula (I), (Ia), a species thereof, or a specified form thereof is co-administered with a SOC agent for breast cancer (e.g., a second line treatment after failure of an aromatase inhibitor or a SERM or SERD such as tamoxifen or fulvestrant.
  • a SOC agent for breast cancer e.g., a second line treatment after failure of an aromatase inhibitor or a
  • An enhancer or SE can be identified by various methods known in the art (see Hinsz et al., Cell, 155:934-947, 2013; McKeown et al., Cancer Discov., 7(10):1136-53, 2017; and PCT/US2013/066957, each of which are hereby incorporated herein by reference in their entireties). Identifying a SE can be achieved by obtaining a biological sample from a patient (e.g., from a biopsy or other source, as described herein).
  • the important metrics for enhancer measurement occur in two dimensions: along the length of the DNA over which genomic markers (e.g., H3K27Ac) are contiguously detected and the compiled incidence of genomic marker at each base pair along that span of DNA, the compiled incidence constituting the magnitude.
  • genomic markers e.g., H3K27Ac
  • the measurement of the area under the curve (“AUC”) resulting from integration of length and magnitude analyses determines the strength of the enhancer.
  • E2F pathway member E2F1, E2F2, E2F3, E2F4, E2F5, E2F6, E2F7, E2F8, CCND1, CCND2, CCND3, CCNE1, or CCNE2
  • a ubiquitous super-enhancer region is the MALAT1 super-enhancer locus (chr11:65263724-65266724) (genome build hg19).
  • ChIP-seq is used to analyze protein interactions with DNA by combining chromatin immunoprecipitation (ChIP) with massively parallel DNA sequencing to identify the binding sites of DNA-associated proteins. It can be used to map global binding sites precisely for any protein of interest.
  • ChIP-on-chip was the most common technique utilized to study these protein-DNA relations. Successful ChIP-seq is dependent on many factors including sonication strength and method, buffer compositions, antibody quality, and cell number (see, e.g., Furey, Nature Reviews Genetics 13:840-852, 2012); Metzker, Nature Reviews Genetics 11:31-46, 2010; and Park, Nature Reviews Genetics 10:669-680, 2009).
  • Genomic markers other than H3K27Ac that can be used to identify SEs using ChIP-seq include P300, CBP, BRD2, BRD3, BRD4, components of the mediator complex (Loven et al., Cell, 153(2):320-334, 2013), histone 3 lysine 4 monomethylated (H3K4me1), and other tissue-specific enhancer tied transcription factors (Smith and Shilatifard, Nature Struct. Mol. Biol., 21(3):210-219, 2014; and Pott and Lieb, Nature Genetics, 47(1):8-12, 2015). Quantification of enhancer strength and identification of SEs can be determined using SE scores (McKeown et al., Cancer Discov. 7(10):1136-1153, 2017; DOI: 10.1158/2159-8290.CD-17-0399).
  • H3K27Ac or other marker ChIP-seq data SE maps of the entire genome of a cell line or a patient sample already exist. One would then simply determine whether the strength or ordinal rank of the enhancer or SE in such maps at the chr8:128628088-128778308 (genome build hg19) locus was equal to or above the pre-determined threshold level. In some embodiments, one would simply determine whether the strength, or ordinal rank of the enhancer or super-enhancer in such maps at the chr1:205399084-205515396 (genome build hg19) locus was equal to or above the pre-determined threshold level.
  • E2F pathway member E2F1, E2F2, E2F3, E2F4, E2F5, E2F6, E2F7, E2F8, CCND1, CCND2, CCND3, CCNE1, or CCNE2
  • E2F pathway member E2F1, E2F2, E2F3, E2F4, E2F5, E2F6, E2F7, E2F8, CCND1, CCND2, CCND3, CCNE1, or CCNE2
  • MALAT1 may differ for different genome builds and/or for different cell types.
  • BCL2-like 1, CDK7, CDK9, CDKN2A, and RB1 or another E2F pathway member that is underexpressed in cancer (E2F1, E2F2, E2F3, E2F4, E2F5, E2F6, E2F7, E2F8, CCND1, CCND2, CCND3, CCNE1, or CCNE2).
  • E2F1, E2F2, E2F3, E2F4, E2F5, E2F6, E2F7, E2F8, CCND1, CCND2, CCND3, CCNE1, or CCNE2 E2F1, E2F2, E2F3, E2F4, E2F5, E2F6, E2F7, E2F8, CCND1, CCND2, CCND3, CCNE1, or CCNE2.
  • chromatin immunoprecipitation (Delmore et al., Cell, 146(6):904-917, 2011), chip array (ChIP-chip), and chromatin immunoprecipitation followed by qPCR (ChIP-qPCR) using the same immunoprecipitated genomic markers and oligonucleotide sequences that hybridize to the chr8:128628088-128778308 (genome build hg19) MYC locus or chr1:205399084-205515396 (genome build hg19) CDK18 locus (for example).
  • the signal is typically detected by intensity fluorescence resulting from hybridization of a probe and input assay sample as with other array-based technologies.
  • a dye that becomes fluorescent after intercalating the double stranded DNA generated in the PCR reaction is used to measure amplification of the template.
  • determination of whether a cell has a BRAF, MYC, CDK1, CDK2, CDK4, CDK6, CDK7, CDK17, CDK18, CDK19, CCNA1, CCNB1, CCNE1, ESR-1, FGFR1, PIK3CA, or certain genes encoding an E2F pathway member (see above) SE strength equal to or above a requisite threshold level is achieved by comparing BRAF, MYC, CDK1, CDK2, CDK4, CDK6, CDK7, CDK17, CDK18, CDK19, CCNA1, CCNB1, CCNE1, ESR-1, FGFR1, PIK3CA, or certain genes encoding an E2F pathway member (see above) enhancer strength in a test cell to the corresponding BRAF, MYC, CDK1, CDK2, CDK4, CDK6, CDK7, CDK17, CDK18, CDK19, CCNA1, CCNB1, CCNE1, ESR-1, FGFR1, PIK3CA, or
  • only primary tumor cell samples from patients are used to determine the threshold level.
  • at least some of the samples in the population will have been tested for responsiveness to a specific CDK7 inhibitor (e.g., a compound of Formula (I), (Ia), a species thereof or a specified form thereof) to establish: (a) the lowest M BRAF, MYC, CDK1, CDK2, CDK4, CDK6, CDK7, CDK17, CDK18, CDK19, CCNA1, CCNB1, CCNE1, ESR-1, FGFR1, PIK3CA, or certain genes encoding an E2F pathway member (see above) enhancer strength of a sample in the population that responds to that specific compound (“lowest responder”); and, optionally, (b) the highest BRAF, MYC, CDK1, CDK2, CDK4, CDK6, CDK7, CDK17, CDK18, CDK19, CCNA1, CCNB1, CCNE1, ESR-1, FGFR
  • a specific CDK7 inhibitor
  • a cutoff of BRAF, MYC, CDK1, CDK2, CDK4, CDK6, CDK7, CDK17, CDK18, CDK19, CCNA1, CCNB1, CCNE1, ESR-1, FGFR1, PIK3CA, or certain genes encoding an E2F pathway member (see above) enhancer strength above which a test cell would be considered responsive to that specific compound is set: i) equal to or up to 5% above the BRAF, MYC, CDK1, CDK2, CDK4, CDK6, CDK7, CDK17, CDK18, CDK19, CCNA1, CCNB1, CCNE1, ESR-1, FGFR1, PIK3CA, or certain genes encoding an E2F pathway member (see above) enhancer strength in the lowest responder in the population; or ii) equal to or up to 5% above the BRAF, MYC, CDK1, CDK2, CDK4, CDK6, CDK7, CDK17, CDK18, CDK19, CC
  • not all of the samples in a population necessarily are to be tested for responsiveness to a specific CDK7 inhibitor (e.g., a compound of Formula (I), (Ia), a species thereof or a specified form thereof), but all samples are measured for BRAF, MYC, CDK1, CDK2, CDK4, CDK6, CDK17, CDK18, CDK19, CCNA1, CCNB1, CCNE1, ESR-1, FGFR1, PICKCA, or certain genes encoding an E2F pathway member (see above) enhancer strength.
  • a specific CDK7 inhibitor e.g., a compound of Formula (I), (Ia), a species thereof or a specified form thereof
  • all samples are measured for BRAF, MYC, CDK1, CDK2, CDK4, CDK6, CDK17, CDK18, CDK19, CCNA1, CCNB1, CCNE1, ESR-1, FGFR1, PICKCA, or certain genes encoding an E2F pathway member (see above) enhancer strength.
  • the samples are rank ordered based on M BRAF, MYC, CDK1, CDK2, CDK4, CDK6, CDK17, CDK18, CDK19, CCNA1, CCNB1, CCNE1, ESR-1, FGFR1, PIK3CA, or certain genes encoding an E2F pathway member (see above) enhancer strength.
  • the cutoff is typically set equal to or is up to 5% above the BRAF, MYC, CDK1, CDK2, CDK4, CDK6, CDK17, CDK18, CDK19, CCNA1, CCNB1, CCNE1, ESR-1, FGFR1, PIK3CA, or certain genes encoding an E2F pathway member (see above) enhancer strength
  • the cutoff is typically set equal to or is up to 5% above the BRAF, MYC, CDK1, CDK2, CDK4, CDK6, CDK17, CDK18, CDK19, CCNA1, CCNB1, CCNE1, ESR-1, FGFR1, PIK3CA, or certain genes encoding an E2F pathway member (see above) enhancer strength in the lowest responder in the population.
  • This cutoff maximizes the number of potential responders.
  • the cutoff is typically set to a value in between the BRAF, MYC, CDK1, CDK2, CDK4, CDK6, CDK17, CDK18, CDK19, CCNA1, CCNB1, CCNE1, ESR-1, FGFR1, PIK3CA, or certain genes encoding an E2F pathway member (see above) enhancer strength
  • the cutoff is typically set to a value in between the BRAF, MYC, CDK1, CDK2, CDK4, CDK6, CDK17, CDK18, CDK19, CCNA1, CCNB1, CCNE1, ESR-1, FGFR1, PIK3CA, or certain genes encoding an E2F pathway member (see above) enhancer strength of the lowest responder and the highest non-responder.
  • the cutoff minimizes the number of false positives.
  • the cutoff is typically set to a value equal to or up to 5% above the BRAF, MYC, CDK1, CDK2, CDK4, CDK6, CDK17, CDK18, CDK19, CCNA1, CCNB1, CCNE1, ESR-1, FGFR1, PIK3CA, or certain genes encoding an E2F pathway member (see above) enhancer strength in the highest non-responder in the population. This method also minimizes the number of false positives.
  • the methods discussed above can be employed to simply determine if a diseased cell (e.g., a cancer cell) from a patient has a SE associated with a biomarker gene described herein (e.g., BRAF, MYC, CDK1, CDK2, CDK4, CDK6, CDK17, CDK18, CDK19, CCNA1, CCNB1, CCNE1, ESR-1, FGFR1, PIK3CA, or certain genes encoding an E2F pathway member (see above) or a protein encoded thereby).
  • a biomarker gene described herein e.g., BRAF, MYC, CDK1, CDK2, CDK4, CDK6, CDK17, CDK18, CDK19, CCNA1, CCNB1, CCNE1, ESR-1, FGFR1, PIK3CA, or certain genes encoding an E2F pathway member (see above) or a protein encoded thereby.
  • a biomarker gene described herein e.g., BRAF,
  • the cell is determined to have a SE associated with the biomarker (e.g., BRAF, MYC, CDK1, CDK2, CDK4, CDK6, CDK17, CDK18, CDK19, CCNA1, CCNB1, CCNE1, ESR-1, FGFR1, PIK3CA, or certain genes encoding an E2F pathway member (see above) or a protein encoded thereby) when the enhancer has a strength that is equal to or above the enhancer associated with MALAT-1.
  • a SE associated with the biomarker e.g., BRAF, MYC, CDK1, CDK2, CDK4, CDK6, CDK17, CDK18, CDK19, CCNA1, CCNB1, CCNE1, ESR-1, FGFR1, PIK3CA, or certain genes encoding an E2F pathway member (see above) or a protein encoded thereby
  • the cell is determined to have a SE associated with BRAF, MYC, CDK1, CDK2, CDK4, CDK6, CDK17, CDK18, CDK19, CCNA1, CCNB1, CCNE1, ESR-1, FGFR1, PIK3CA, or certain genes encoding an E2F pathway member (see above) when the BRAF ⁇ , MYC ⁇ , CDK1 ⁇ , CDK2 ⁇ , CDK4 ⁇ , CDK6 ⁇ , CDK17 ⁇ , CDK18 ⁇ , CDK19 ⁇ , CCNA1 ⁇ , CCNB1 ⁇ , CCNE1 ⁇ , ESR ⁇ 1 ⁇ , FGFR1 ⁇ , PIK3CA ⁇ , or certain genes encoding an E2F pathway member- (see above) associated enhancer has a strength that is at least 10-fold greater than the median strength of all of the enhancers in the cell.
  • the cell is determined to have a SE associated with an aforementioned gene when the gene-associated enhancer has a strength that is above the point where the slope of the tangent is 1 in a rank-ordered graph of strength of each of the enhancers in the cell.
  • the cutoff value for enhancer strength can be converted to a prevalence cutoff, which can then be applied to biomarker RNA levels (e.g., CDK18 mRNA) levels to determine a mRNA cutoff value in a given mRNA assay.
  • biomarker RNA levels e.g., CDK18 mRNA
  • biomarker mRNA levels in a patient are compared, using the same assay, to the same gene of interest/biomarker mRNA levels in a population of patients having the same disease or condition to identify likely responders to a compound of Formula (I), (Ia), a species thereof, or a specified form thereof.
  • Analogous comparisons can be made when another feature of the biomarker is selected for analysis (e.g., its copy number, chromosomal location, primary RNA level, or expressed protein level).
  • a biomarker e.g., CDK18, CDK19, and CCNE1 correlates with (e.g., is one whose mRNA expression correlates with) responsiveness to a compound of the invention
  • the inhibitor e.g., a compound of Formula (I), (Ia), a species thereof, or specified form thereof
  • the inhibitor e.g., a compound of Formula (I), (Ia), a species thereof, or specified form thereof
  • a cutoff of biomarker mRNA level above which a test cell would be considered responsive to that specific compound is set: i) equal to or up to 5% above the level (e.g., the mRNA level) in the lowest mRNA responder in the population; or ii) equal to or up to 5% above the level (e.g., the mRNA level) in the highest mRNA non-responder in the population; or iii) a value in between the level (e.g., mRNA level) of the lowest responder (e.g., lowest mRNA responder) and the highest responder (e.g., highest mRNA) non-responder in the population.
  • mRNA levels positively correlate with sensitivity to a compound of Formula (I), (Ia), a species thereof or a specified form thereof not all of the samples in a population need to be tested for responsiveness to the compound, but all samples are measured for the gene of interest mRNA levels.
  • the samples are rank ordered based on gene of interest mRNA levels. The choice of which of the three methods set forth above to use to establish the cutoff will depend upon the difference in gene of interest mRNA levels between the lowest mRNA responder and the highest mRNA non-responder in the population and whether the cutoff is designed to minimize false positives or maximize the potential number of responders.
  • the cutoff is typically set equal to or up to 5% above the mRNA level in the lowest mRNA responder.
  • the cutoff is typically set to a value in between the mRNA levels of the lowest mRNA responder and the highest mRNA non-responder.
  • the cutoff is typically set to a value equal to or up to 5% above the mRNA levels in the highest mRNA non-responder in the population.
  • a biomarker is one whose mRNA expression inversely correlates with responsiveness to a compound of Formula (I), (Ia), a species thereof, or a specified form thereof (i.e., BCL-xL, CDK7, CDK9, or an RB1 family member)
  • at least some of the samples in the population will have been tested for responsiveness to the compound in order to establish: (a) the highest mRNA level of a sample in the population that responds to that specific compound (“highest mRNA responder”); and, optionally, (b) the lowest mRNA level of a sample in the population that does not respond to that specific compound (“lowest mRNA non-responder”).
  • a cutoff of mRNA level above which a test cell would be considered responsive to that specific compound is set: i) equal to or up to 5% below the mRNA level in the highest mRNA responder in the population; or ii) equal to or up to 5% below the mRNA level in the lowest mRNA non-responder in the population; or iii) a value in between the mRNA level of the lowest mRNA non-responder and the highest mRNA responder and in the population.
  • mRNA levels inversely correlate with sensitivity to a compound of the invention
  • samples are measured for the gene of interest mRNA levels.
  • the samples are rank ordered based on gene of interest mRNA levels. The choice of which of the three methods set forth above to use to establish the cutoff will depend upon the difference in gene of interest mRNA levels between the highest mRNA responder and the lowest mRNA non-responder in the population and whether the cutoff is designed to minimize false positives or maximize the potential number of responders.
  • the cutoff is typically set equal to or up to 5% below the mRNA level in the highest mRNA responder.
  • the cutoff is typically set to a value in between the mRNA levels of the highest mRNA responder and the lowest mRNA non-responder.
  • the cutoff is typically set to a value equal to or up to 5% below the mRNA levels in the lowest mRNA non-responder in the population.
  • the cutoff for CDK18 mRNA levels may be determined using the prevalence cutoff established based on CDK18 enhancer strength, as described above.
  • a population is measured for mRNA levels and the prior determined prevalence cutoff is applied to that population to determine an mRNA cutoff level.
  • a rank-order standard curve of CDK18 mRNA levels in a population is created, and the pre-determined prevalence cutoff is applied to that standard curve to determine the CDK18 mRNA cutoff level.
  • the cutoff mRNA level value(s) obtained for the population is converted to a prevalence rank and the mRNA level cutoff is expressed as a percent of the population having the cutoff value or higher, e.g., a prevalence cutoff.
  • a patient can be identified as likely to respond well to a compound of Formula (I), (Ia), a species thereof, or a specified form thereof if the state of BRAF, MYC, CDK1, CDK2, CDK4, CDK6, CDK7, CDK17, CDK18, CDK19, CCNA1, CCNB1, CCNE1, ESR-1, FGFR1, PIK3CA, or certain genes encoding an E2F pathway member (see above) as determined by, e.g., RNA (e.g., mRNA levels) in a biological sample from the patient) corresponds to (e.g., is equal to or greater than) a prevalence rank in a population of about 80%, 79%, 78%, 77%, 76%, 75%, 74%, 73%, 72%, 71%, 70%, 69%, 68%, 67%, 66%, 65%, 64%, 63%, 62%, 61%, 60%, 59%, 58%, 57%, 56%, 55%, 54%, 4
  • a patient can be identified as likely to respond well to a compound of Formula (I), (Ia), a species thereof, or a specified form thereof if the state of BCL2-like 1, CDK7, CDK9, CDKN2A, and RB (as determined by, e.g., RNA (e.g., mRNA) levels or corresponding protein levels in a biological sample from the patient) is below a prevalence rank in a population of about 80%, 79%, 78%, 77%, 76%, 75%, 74%, 73%, 72%, 71%, 70%, 69%, 68%, 67%, 66%, 65%, 64%, 63%, 62%, 61%, 60%, 59%, 58%, 57%, 56%, 55%, 54%, 43%, 42%, 51%, 50%, 49%, 48%, 47%, 46%, 45%, 44%, 43%, 42%, 41%, 40%, 39%, 38%, 37%, 36%, 35%, 34%, 33%, 32%
  • a population may be divided into three groups: responders, partial responders and non-responders, and two cutoff values (or thresholds) or prevalence cutoffs (or thresholds) are set or determined.
  • the partial responder group may include responders and non-responders as well as those patients whose response to a compound of Formula (I), (Ia), a species thereof, or a specified form thereof was not as high as the responder group. This type of stratification may be particularly useful when, in a population, the highest mRNA non-responder has an mRNA level that is greater than that of the lowest mRNA responder.
  • the cutoff level or prevalence cutoff between responders and partial responders is set equal to or up to 5% above the CDK18 or CDK19 mRNA level of the highest CDK18 or CDK19 mRNA non-responder; and the cutoff level or prevalence cutoff between partial responders and non-responders is set equal to or up to 5% below the CDK18 or CDK19 mRNA level of the lowest CDK18 or CDK19 mRNA responder.
  • this type of stratification may be useful when the highest mRNA responder has a mRNA level that is lower than that of the lowest mRNA non-responder.
  • the cutoff level or prevalence cutoff between responders and partial responders is set equal to or up to 5% below the mRNA level of the lowest mRNA non-responder; and the cutoff level or prevalence cutoff between partial responders and non-responders is set equal to or up to 5% above the mRNA level of the highest mRNA responder.
  • the determination of whether partial responders should be administered a compound of Formula (I), (Ia), a species thereof, or a specified form thereof will depend upon the judgment of the treating physician and/or approval by a regulatory agency.
  • RNA sequencing e.g., RNA-seq
  • RNA hybridization and signal amplification as utilized with RNAscope® (Advanced Cell Diagnostics)
  • Northern blot mRNA expression values for various genes in various cell types are publicly available (see, e.g., broadinstitute.org/ccle; and Barretina et al., Nature, 483:603-607, 2012).
  • the state of a biomarker (as assessed, for example, by the level of RNA transcripts) in both the test biological sample (i.e., from the patient) and the reference standard or all members of a population is normalized before comparison. Normalization involves adjusting the determined level of an RNA transcript by comparison to either another RNA transcript that is native to and present at equivalent levels in both of the cells (e.g., GADPH mRNA, 18S RNA), or to a fixed level of exogenous RNA that is “spiked” into samples of each of the cells prior to super-enhancer strength determination (Lovén et al., Cell, 151(3):476-82, 2012; Kanno et al., BMC Genomics 7:64, 2006; Van de Peppel et al., EMBO Rep., 4:387-93, 2003).
  • a patient e.g., a human suffering from a cancer described herein and identified as described herein based on biomarker status may have been determined to be resistant (or to be acquiring resistance after some initial efficacy) to a therapeutic agent that was administered prior to the compound of Formula (I), (Ia), a species thereof, or a specified form thereof.
  • the cancer may be resistant or refractory to a chemotherapeutic agent, e.g., a Bcl-2 inhibitor such as venetoclax, a BET inhibitor, a CDK4/6 inhibitor such as palbociclib or ribociclib, a CDK9 inhibitor such as alvocidib, a FLT3 inhibitor, a MEK inhibitor such a trametinib, a PARP inhibitor, such as olaparib or niraparib, a PI3K inhibitor, such as alpelisib or capecitabine, a platinum-based therapeutic agent such as cisplatin, oxaliplatin, nedaplatin, carboplatin, phenanthriplatin, picoplatin, satraplatin (JM216), or triplatin tetranitrate, a SERM, such as tamoxifen faloxifene, or toremifene, or a steroid receptor degrading agent (e.g.,
  • the methods encompass the use of or administration of a compound of Formula (I), (Ia), a species thereof or a specified form thereof, in combination with a SERD, such as fulvestrant, to treat a cancer (e.g., a breast cancer (e.g., an ER+ breast cancer)) resistant to treatment with a CDK4/6 inhibitor such as palbociclib or ribociclib.
  • a cancer e.g., a breast cancer (e.g., an ER+ breast cancer)
  • a CDK4/6 inhibitor such as palbociclib or ribociclib.
  • the prior therapeutic agent may be a platinum-based anti-cancer agent administered as a monotherapy or in combination with a SOC agent.
  • Most cancer patients eventually develop resistance to platinum-based therapies by one or more of the following mechanisms: (i) molecular alterations in cell membrane transport proteins decrease uptake of the platinum agent; (ii) molecular alterations in apoptotic signaling pathways that prevent a cell from inducing cell death; (iii) molecular alterations of certain genes (e.g. BRCA1/2, CHEK1, CHEK2, RAD51) that restore the ability of the cell to repair platinum agent-induced DNA damage.
  • K. N. Yamamoto et al., 2014, PloS ONE 9(8):e105724 The term “molecular alterations” includes increased or decreased mRNA expression from the genes involved in these functions; increased or decreased expression of protein from such genes; and mutations in the mRNA/proteins expressed from those genes.
  • Resistance is typically determined by disease progression (e.g., an increase in tumor size and/or numbers) during treatment or a decrease in the rate of shrinkage of a tumor.
  • a patient will be considered to have become resistant to a platinum-based agent when the patient's cancer responds or stabilizes while on treatment, but which progresses within 1-6 months following treatment with the agent. Resistance can occur after any number of treatments with platinum agents.
  • disease progression occurs during, or within 1 month of completing treatment. In this case, the patient is considered to have never demonstrated a response to the agent. This is also referred to a being “refractory” to the treatment. Resistance may also be determined by a treating physician when the platinum agent is no longer considered to be an effective treatment for the cancer.
  • the patient is or has been determined to be resistant to treatment with a CDK4/6 inhibitor administered as a monotherapy or in combination with a SOC agent.
  • CDK4/6 inhibitors in cancer are known to block entry into S phase of the cell cycle by inducing G1 arrest.
  • Resistance to CDK4/6 inhibitors in cancer has been shown to be mediated, in part, by molecular alterations that: 1) enhance CDK4/6 activity, such as amplifications of CDK6, CCND1, or FGFR1 (Formisano et al., SABCS 2017, Publication Number GS6-05; Cruz et al., SABCS 2017 Publication Number PD4-05), or 2) reactivate cell cycle entry downstream of CDK4/6, such as RB1 loss and CCNE1 amplification (Condorelli, Ann. Oncol., 2017 PMID: 29236940; Herrera-Abreu, Cancer Research 2016 PMID: 27020857).
  • CDK4/6 inhibitors such as palbociclib, ribociclib or abemaciclib, are administered until disease progression is observed.
  • a patient will be considered to have become resistant to a CDK4/6 inhibitor when the patient's cancer initially responds or stabilizes while on treatment, but which ultimately begins to progress while still on treatment.
  • a patient will be considered to be resistant (or refractory) to treatment with a CDK4/6 inhibitor if the cancer progresses during treatment without demonstrating any significant response or stabilization. Resistance may also be determined by a treating physician when the CDK4/6 inhibitor is no longer considered to be an effective treatment for the cancer.
  • any of the specified forms of a compound of Formula (I), (Ia), or a species thereof can be included in a pharmaceutical composition used or administered (e.g., in an effective amount (e.g., a therapeutically effective amount) according to a method of the invention.
  • Pharmaceutical compositions useful in the methods of the invention can be prepared by relevant methods known in the art of pharmacology.
  • such preparatory methods include the steps of bringing a compound described herein, including compounds of Formula (I), (Ia), a species thereof, or a specified form thereof (e.g., a pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, or isotopic form thereof) into association with a carrier and/or one or more other active ingredients (e.g., a second agent described herein) and/or accessory ingredients, and then, if necessary and/or desirable, shaping and/or packaging the product into a desired single-dose or multi-dose unit (e.g., for oral dosing).
  • a carrier and/or one or more other active ingredients e.g., a second agent described herein
  • shaping and/or packaging the product into a desired single-dose or multi-dose unit (e.g., for oral dosing).
  • the accessory ingredient may improve the bioavailability of a compound of Formula (I), (Ia), a species thereof, or a specified form thereof, may reduce and/or modify its metabolism, may inhibit its excretion, and/or may modify its distribution within the body (e.g., by targeting a diseased tissue (e.g., a tumor).
  • the pharmaceutical compositions can be packaged in various ways, including in bulk containers and as single unit doses (containing, e.g., discrete, predetermined amounts of the active agent) or a plurality thereof, and any such packaged or divided dosage forms are within the scope of the invention.
  • the amount of the active ingredient can be equal to the amount constituting a unit dosage or a convenient fraction of a dosage such as, for example, one-half or one-third of a dose.
  • Relative amounts of the active agent/ingredient, the pharmaceutically acceptable carrier(s), and/or any additional ingredients in a pharmaceutical composition of the invention can vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered and the disease to be treated.
  • the composition may comprise between about 0.1% and 99.9% (w/w or w/v) of an active agent/ingredient.
  • Pharmaceutically acceptable carriers useful in the manufacture of the pharmaceutical compositions described herein are well known in the art of pharmaceutical formulation and include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils.
  • Pharmaceutically acceptable carriers useful in the manufacture of the pharmaceutical 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, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
  • ion exchangers alumina, aluminum stearate, lecithin
  • serum proteins such as human serum albumin
  • buffer substances such as phosphates, glycine
  • compositions used as described herein may be administered orally.
  • Such orally acceptable dosage forms may be solid (e.g., a capsule, tablet, sachet, powder, granule, and orally dispersible film) or liquid (e.g., an ampoule, semi-solid, syrup, suspension, or solution (e.g., aqueous suspensions or dispersions and solutions).
  • carriers commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, can also be included.
  • useful diluents include lactose and dried cornstarch.
  • sweetening, flavoring or coloring agents may also be added.
  • an oral formulation can be formulated for immediate release or sustained/delayed release and may be coated or uncoated.
  • a provided composition can also be micro-encapsulated.
  • compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles. Formulations can also be prepared for subcutaneous, intravenous, intramuscular, intraocular, intravitreal, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intraperitoneal intralesional and by intracranial injection or infusion techniques. Preferably, the compositions are administered orally, subcutaneously, intraperitoneally or intravenously.
  • Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • a non-toxic parenterally acceptable diluent or solvent for example as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • compositions suitable for administration to humans are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by one of ordinary skill in the art that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification.
  • Compounds described herein are typically formulated in dosage unit form, e.g., single unit dosage form, for ease of administration and uniformity of dosage.
  • the specific therapeutically or prophylactically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.
  • the amount of a compound required to achieve an optimum clinical outcome can vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects, cancer to be treated, identity of the particular compound(s) to be administered, and mode of administration.
  • the desired dosage can be delivered two or three times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks.
  • the desired dosage can be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).
  • an effective amount of a compound for administration one or more times a day (e.g., once) to a 70 kg adult human may comprise about 1-100 mg, about 1-50 mg, about 1-35 mg (e.g., about 1-5, 1-10, 1-15, 1-20, 1-25, or 1-30 mg), about 2-20 mg, about 3-15 mg or about 10-30 mg (e.g., 10-20 or 10-25 mg).
  • the dosages provided in this disclosure can be scaled for patients of differing weights or body surface and may be expressed per m 2 of the patient's body surface.
  • compositions of the invention may be administered once per day.
  • the dosage of a compound of Formula (I), (Ia), a species thereof or a specified form thereof can be about 1-100 mg, about 1-50 mg, about 1-25 mg, about 2-20 mg, about 5-15 mg, about 10-15 mg, or about 13-14 mg.
  • a composition of the invention may be administered twice per day.
  • the dosage of a compound of Formula I or a subgenus or species thereof for each administration is about 0.5 mg to about 50 mg, about 0.5 mg to about 25 mg, about 0.5 mg to about 1 mg, about 1 mg to about 10 mg, about 1 mg to about 5 mg, about 3 mg to about 5 mg, or about 4 mg to about 5 mg.
  • kits configured for treating cancer that include a compound of Formula (I), (Ia), a species thereof, or a specified form thereof and, optionally, an additional/second therapeutic agent (e.g., second and third agents) selected from the second/additional agents described herein.
  • an additional/second therapeutic agent e.g., second and third agents
  • the second/additional agent can be: (a) a Bcl-2 inhibitor or dual Bcl-2/BCL-xL inhibitor, (b) a CDK inhibitor (e.g., a CDK4/6, CDK7, or CDK9 inhibitor), (c) a Flt3 inhibitor, (d) a PARP inhibitor, (e) a BET inhibitor, (f) an aromatase inhibitor, (g) a SERM, SERD, or estrogen suppressant, (h) a MEK inhibitor, or (i) a PI3 kinase inhibitor, which, as noted, may be selected from those disclosed herein.
  • a CDK inhibitor e.g., a CDK4/6, CDK7, or CDK9 inhibitor
  • a Flt3 inhibitor e.g., a Flt3 inhibitor
  • a PARP inhibitor e.g., a BET inhibitor
  • an aromatase inhibitor e.g., a SERM, SERD, or estrogen
  • the kit can include optional instructions for: (a) reconstituting (if necessary) a compound of Formula (I), (Ia), a species thereof, or a specified form thereof and/or the second therapeutic agent; (b) administering each of the compound of Formula (I), (Ia), a species thereof, or a specified form thereof and/or the second therapeutic agent; and/or (c) a list of specific cancers for which the kit is useful or diagnostic methods by which they may be determined.
  • the kits can also include any type of paraphernalia useful in administering the active agent(s) contained therein (e.g., tubing, syringes, needles, sterile dressings, tape, and the like).
  • kits whether configured to deliver a monotherapy consisting of a compound of Formula (I), (Ia), a species thereof, or a specified variant thereof, or a combination therapy including an additional/second agent selected from any one of those described herein, find utility in the diagnostic and treatment methods described herein.
  • the first and second agents will be in separate vessels (e.g., with the first agent confined to a first container and the second agent confined to a second container) and/or formulated in a pharmaceutically acceptable composition, optionally in unit dosage form, that includes the first agent, the second agent, and a pharmaceutically acceptable carrier.
  • kits include a written insert or label with instructions to use the two (or more) therapeutic agents in a patient suffering from a cancer (e.g., as described herein) and identified as amenable to treatment by a method described herein.
  • the instructions may be adhered or otherwise attached to a vessel or vessels comprising the therapeutic agents.
  • the instructions and the vessel(s) can be separate from one another but present together in a single kit, package, box, bag, or other type of container.
  • the written instructions can specify and direct the user to a website or other media.
  • the instructions in the kit will typically be mandated or recommended by a governmental agency approving the therapeutic use of the combination (e.g., in a patient population identified as described herein).
  • the instructions may optionally comprise dosing information for each therapeutic agent, the types of cancer for which treatment of the combination was approved or may be prescribed, physicochemical information about each of the therapeutics, pharmacokinetic information about each of the therapeutics, drug-drug interaction information, or diagnostic information (e.g., based on a biomarker or a method of identifying a patient for treatment as described herein).
  • the kits of the invention can also include reagents useful in the diagnostic methods described herein.
  • the compounds described herein can be prepared from readily available starting materials and according to the synthetic protocols described below. Alternatively, one of ordinary skill in the art may readily modify the disclosed protocols. For example, it will be appreciated that where process conditions (e.g., reaction temperatures, reaction times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used. Additionally, and as will be apparent to one of ordinary skill in the art, protecting groups may be used to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups and guidance for their introduction and removal are disclosed by Greene et al. ( Protecting Groups in Organic Synthesis , Second Edition, Wiley, New York, 1991, and references cited therein).
  • Example 1 Synthesis of Benzyl (2R, 5R)-5-amino-2-methyl-piperidine-1-carboxylate and benzyl (2S, 5S)-5-amino-2-methyl-piperidine-1-carboxylate
  • Step 1 Benzyl 5-(tert-butoxycarbonylamino)-2-methyl-piperidine-1-carboxylate
  • Step 2 Benzyl (2R, 5R)-5-amino-2-methyl-piperidine-1-carboxylate and benzyl (2S, 5S)-5-amino-2-methyl-piperidine-1-carboxylate
  • Step 1 Benzyl (2S, 5S)-5-[[4-(7-chloro-6-cyano-1H-indol-3-yl)-5-(trifluoromethyl) pyrimidin-2-yl] amino]-2-methyl-piperidine-1-carboxylate
  • Step 2 Benzyl (2S, 5S)-5-[[4-(6-cyano-7-dimethylphosphoryl-1H-indol-3-yl)-5-(trifluoromethyl) pyrimidin-2-yl]amino]-2-methyl-piperidine-1-carboxylate
  • Step 3 7-dimethylphosphoryl-3-[2-[[(3S, 6S)-6-methyl-3-piperidyl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]-1H-indole-6-carbonitrile
  • Step 5 (S)-7-Bromo-3-(2-((6,6-dimethylpiperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carbonitrile
  • Step 6 (S)-7-(dimethylphosphoryl)-3-(2-((6-dimethylpiperidin-3-yl)amino)-5-(trifluoromethyl)-pyrimidin-4-yl)-1H-indole-6-carbonitrile
  • Dimethylphosphine oxide (73 mg, 0.912 mmol) was dissolved in anhydrous DMF (1 mL), and the solution was degassed before combining with the other reactants in a microwave vial.
  • the sealed vial with the reaction mixture was then submitted to heat in a microwave reactor at 150° C. for 45 minutes.
  • the reaction mixture was cooled to room temperature, loaded directly onto a C18 column, and purified by reverse phase chromatography (MeCN in aqueous 10 mM ammonium formate pH 3.8, 15 to 35% gradient). The title compound was obtained as an off-white solid (76 mg, 0.155 mmol, 42% yield).
  • Step 3 (S)-1-tert-butyl 2-methyl 4,4-dimethyl-5-oxopyrrolidine-1,2-dicarboxylate
  • Step 4 tert-butyl N-[(1S)-4-hydroxy-1-(hydroxymethyl)-3,3-dimethyl-butyl]carbamate
  • Step 5 [(2S)-2-(tert-butoxycarbonylamino)-4,4-dimethyl-5-methylsulfonyloxy-pentyl]methanesulfonate
  • Step 1 (S)-3-(2-((1-benzyl-5,5-dimethylpiperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-bromo-1H-indole-6-carbonitrile
  • Step 2 (S)-3-(2-((1-benzyl-5,5-dimethylpiperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-7-(dimethylphosphoryl)-1H-indole-6-carbonitrile
  • Dimethylphosphine oxide (39.2 mg, 0.494 mmol) was dissolved in anhydrous DMF (1 mL), and the solution was degassed before combining with the other reactants in a microwave vial.
  • the sealed vial with the reaction mixture was then submitted to heat in a microwave reactor at 145° C. for 45 minutes.
  • the reaction mixture was then cooled to room temperature, diluted with 2-MeTHF and washed with saturated aqueous NaHCO 3 and brine.
  • the organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo before the residue was purified by reverse phase chromatography on C18 (MeCN in aqueous 10 mM ammonium formate pH 3.8, 0 to 100% (gradient).
  • the title compound was obtained as a pale brown oil (58.0 mg, 0.10 mmol, 24% yield).
  • Step 3 (S)-7-(dimethylphosphoryl)-3-(2-((5,5-dimethylpiperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole-6-carbonitrile
  • test compounds variant concentrations from 10 ⁇ M down to 0.508 nM in a series of 3-fold serial dilutions
  • active CDK protein with the indicated cyclin, listed below for each CDK
  • ATP at either the K m concentrations listed below for each CDK/cyclin or 2 mM ATP
  • substrate peptide listed below
  • buffer 2-(N-morpholino)ethanesulfonate (MES buffer, 20 mM), pH 6.75, 0.01% (v/v) Tween 20 detergent, 0.05 mg/mL bovine serum albumin (BSA), and 2% DMSO.
  • CDK7 inhibition assay used CDK7/Cyclin H/MAT1 complex (6 nM) and “5-FAM-CDK7tide” peptide substrate (2 ⁇ M, synthesized fluorophore-labeled peptide with the sequence 5-FAM-YSPTSPSYSPTSPSYSPTSPSKKKK (SEQ ID NO:1), where “5-FAM” is 5-carboxyfluorescein) with 6 mM MgCl2 in the buffer composition listed above where the apparent ATP K m for CDK7/Cyclin H/MAT1 under these conditions is 50 ⁇ M.
  • the CDK9 inhibition assay used CDK9/Cyclin T1 complex (8 nM) and “5-FAM-CDK9tide” peptide substrate (2 ⁇ M, synthesized fluorophore-labeled peptide with the sequence: 5-FAM-GSRTPMY-NH 2 (SEQ ID NO:2), where 5-FAM is defined above and NH 2 signifies a C-terminal amide with 10 mM MgCl 2 in the buffer composition listed above.
  • the CDK12 inhibition assay used CDK12 (aa686-1082)/Cyclin K complex (50 nM) and “5-FAM-CDK9tide” (2 ⁇ M) as defined above, with 2 mM MgCl 2 in the buffer composition above.
  • the CDK2 inhibition assay used CDK2/Cyclin E1 complex (0.5 nM) and “5-FAM-CDK7tide” (2 ⁇ M) as defined above, with 2 mM MgCl 2 in the buffer composition listed
  • the incubation period at 27° C. for each CDK inhibition assay was chosen such that the fraction of phosphorylated peptide product produced in each assay, relative to the total peptide concentration, was approximately 20% ( ⁇ 5%) for the uninhibited kinase (35 minutes for CDK7, 35 minutes for CDK2, 3 hours for CDK12, and 15 minutes for CDK9). In cases where the compound titrations were tested and resulted in inhibition of peptide product formation, these data were fit to produce best-fit IC 50 values.
  • K d ⁇ ( M ) k off ⁇ ( s - 1 ) k o ⁇ n ⁇ ( M - 1 ⁇ s - 1 ) .
  • CDK7 Compound selectivity for CDK7 over CDK2, CDK9, or CDK12 were determined based on the ratios of K i values for the off-target CDKs relative to the direct compound binding K d for CDK7 measured by SPR according to:
  • each of the compounds of the invention is at least 1300-fold and up to 40,000-fold more specific for CDK7 than for the other CDKs tested.
  • the HCC70 cell line was derived from human TNBC, and we tested representative compounds of the invention, at different concentrations (from 4 ⁇ M to 126.4 ⁇ M; 0.5 log serial dilutions), for their ability to inhibit the proliferation of those cells. More specifically, we tested the same compounds tested above for CDK7 selectivity (the structures of which are shown in FIG.
  • CDK inhibitors dinaciclib or N-((1S,3R)-3-((5-chloro-4-(1H-indol-3-yl) pyrimidin-2-yl)amino)cyclohexyl)-5-((E)-4-(dimethylamino)but-2-enamido)picolinamide
  • triptolide triptolide
  • the cells were grown in ATCC-formulated RPMI-1640 medium (ATCC 30-2001) supplemented with 10% fetal bovine serum (FBS), at 37° C. in a humidified chamber in the presence of 5% CO 2 .
  • mice were treated with either Compound 101, QD (6 mg/kg, once daily, by mouth); fulvestrant, SC (2.5 mg/kg, once weekly dosing, by subcutaneous injection); palbociclib, QD (50 mpk, once daily, by mouth) or in combination of Compound 101 (6 mg/kg, once daily, by mouth) and fulvestrant (2.5 mg/kg, once weekly, by subcutaneous injection) over the course of 28 days, followed by 21 days of observation.
  • TGI Tumor growth inhibition
  • the combination of Compound 101 and fulvestrant induced significant TGI (89%), with no evident tumor regrowth up to 21 days after dosing cessation, distinguishing the observed effects from Compound 101 (83%), fulvestrant (60%) or palbociclib (21%) when administered as single agents. Additionally, the combination of Compound 101 and fulvestrant was superior to the SOC combination of palbociblib and fulvestrant (75%).
  • FIG. 2 illustrates the TGI results from the palbociclib resistant HR+BC PDX model ST1799
  • FIG. 3 illustrates the TGI results from the palbociclib and fulvestrant resistant HR+BC PDX model ST941.
  • BR5010 modeling TNBC
  • LU5178 modeling small cell lung cancer (SCLC)
  • OV15398 modeling high grade serous ovarian cancer (HGSOC)
  • ST390 modeling pancreatic ductal adenocarcinoma (PDAC)
  • TNBC pancreatic ductal adenocarcinoma
  • Compound 101 was orally administered to tumor-bearing NOD/SCID mice at 10 mg/kg QD or 5 mg/kg BID for 21 days.
  • the % regression was calculated as: (Mean TV Compound 101 @ EOT)/(Mean TV Compound 101 @ Day 0) ⁇ 100. The same calculations were used for end of study (day 42). The results are shown in FIG. 4 . These results demonstrate deep and sustained TGI, including regressions, at well tolerated doses, in a variety of tumor types. Dose-dependent transcriptional responses in xenograft tissue were observed within 4 hours of dosing and were sustained for 24 hours. Similar TGI was seen when the same total dose was administered either QD or BID in the TNBC PDX model, suggesting that the effect was AUC or C min driven.
  • cancer cell lines from HR+ breast cancers (lines T47D; PIK3CA p.H1047R, MCF7; PIK3CA p.E545K), SCLC, (NCI-H1048) and CRCs (lines RKO; BRAF p.V600E, SW480; KRAS p.G12V) were grown to 70% confluency in their media of preferences based on the manufacturer recommendations.
  • SCLC cell line NCI-H1048
  • Compound 101 was tested in combination with SOC chemotherapy agents gemcitabine (a DNA synthesis inhibitor) and carboplatin (a DNA damage agent).
  • CRC cell line RKO; BRAF p.V600E
  • SOC chemotherapy agent oxaliplatin a DNA damage agent
  • Compound 101 was tested in combination with the selective MAPK pathway inhibitor trametinib in two CRC cell lines harboring MAPK pathway alterations; RKO (BRAF p.V600E mutant) and SW480 (KRAS p.G12V mutant).
  • SOC agent capecitabine an antimetabolite
  • HR+MCF-7 cells In the HR+ cell lines MCF7 and T47D, which have activating mutations in the PIK3CA kinases, Compound 101 was tested in combination with the PIK3CA selective inhibitor alpelisib.
  • Compound 101 was plated in across from left to right in a high to low concentration (8 columns), and the varying concentrations of carboplatin or oxaliplatin (TEST) plated in synergy wells from top to bottom (7 rows). Concentrations were selected to cover the full isobologram of activity based on activity of single agents. Single agents were plated in dose in two columns, with a third separate column of just DMSO/vehicle treated wells. A separate plate for each cell line was seeded to allow for determination of a “Time Zero”/“Day Zero” number of cells to parse the differential cytostatic vs cytotoxic effects. On the day compounds were added, viability of the time zero plate was determined to identify growth inhibition from cell killing effects.
  • Compound 101 with SOC chemotherapy (gemcitabine or carboplatin in SCLC, oxaliplatin in CRC, or capecitabine in HR+ breast cancer) showed synergy and was superior to either agent alone.
  • SOC chemotherapy gemcitabine or carboplatin in SCLC, oxaliplatin in CRC, or capecitabine in HR+ breast cancer
  • the combination of Compound 101 with the targeted agent trametinib, a selective MAPK pathway inhibitor approved for the treatment of BRAF p.V600E mutant melanoma and NSCLC show significant synergy in BRAF p.V600E mutant CRC as well as in KRAS p.G12V mutant CRC, which harbors a different mutation within the MAPK pathway.
  • Dosing was initiated when tumors were 150-300 mm 3 . Mice were treated with either Compound 101, QD (6 or 10 mg/kg once daily, by mouth) or BID (3 or 5 mg/kg twice daily, by mouth) over the course of 21 days, followed by 21 days of observation.
  • TGI was calculated on the last day of dosing using the formula: TGI (V c1 ⁇ V t1 )/(V c0 ⁇ V t0 ), where V c1 and V t1 are the mean volumes of control and treated groups at the time of tumor extraction, while V c0 and V t0 are the same groups at the start of dosing.
  • FATHMM-MLK was also used to annotate variant effects. Variants that met the following qualifications were included in sample characterizations: (1) variant is located in a protein-coding gene; (2) variant affects protein sequence or results in a frameshift; (3) missense mutations are classified as damaging by SIFT, PolyPhen, or FATHMM-MLK ( ⁇ 0.75); (4) variant allele frequency is ⁇ 10%. Copy-number (CN) variation across capture regions were called using CNVkit (v0.9.1), and CNs for individual genes were calculated by using the mean CN across its capture regions. For model LU5210 mutation/CNV data was made available from WES data provided by the PDX vendor (Crown Biosciences Inc.).
  • Compound 101 induced at least 50% TGI at the end of the 21-day dosing period in all models.
  • Compound 101 responses were deep (>95% TGI or regression) and sustained, with no evidence of tumor regrowth for 21 days after treatment discontinuation (see FIG. 6 ).
  • Compound 101 was well tolerated, with no evident body weight loss at all once-daily doses tested, indicating that the MTD is above 10 mg/kg once daily in tumor-bearing mice. Deep and sustained responses were observed in each indication tested and were associated with alterations in the RB pathway including RB1 deletion or mutation, CDKN2A deletion, or CCNE1 amplification ( FIG. 7 ).

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210403495A1 (en) * 2018-11-01 2021-12-30 Syros Pharmaceuticals, Inc. Inhibitors of cyclin-dependent kinase 7 (cdk7)
US11945785B2 (en) 2021-12-30 2024-04-02 Biomea Fusion, Inc. Pyrazine compounds as inhibitors of FLT3

Families Citing this family (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BR112019000716A2 (pt) * 2016-07-13 2019-05-07 Syros Pharmaceuticals Inc inibidores de quinase dependente de ciclina (cdk7)
AU2019209470A1 (en) 2018-01-16 2020-08-13 Syros Pharmaceuticals, Inc. Inhibitors of cyclin-dependent kinase 7 (CDK7)
AU2019209475A1 (en) 2018-01-16 2020-08-20 Syros Pharmaceuticals, Inc. Inhibitors of cyclin-dependent kinase 7 (CDK7)
CA3156610A1 (en) * 2019-10-29 2021-05-06 J. Graeme HODGSON Methods of treating cancer in biomarker-identified patients with inhibitors of cyclin-dependent kinase 7 (cdk7)
WO2021243280A2 (en) * 2020-05-29 2021-12-02 Syros Pharmaceuticals, Inc. Methods of treating cancer in patients with an anomalous kras gene or deletions within chromosome 9
CN112661745A (zh) * 2020-07-24 2021-04-16 浙江同源康医药股份有限公司 用作cdk7激酶抑制剂的化合物及其应用
CN114249712A (zh) * 2020-09-24 2022-03-29 广州费米子科技有限责任公司 嘧啶基衍生物、其制备方法及其用途
CA3195794A1 (en) * 2020-10-16 2022-04-21 Syros Pharmaceuticals, Inc. Dosing regimens for cyclin?dependent kinase 7 (cdk7) inhibitors
WO2022089444A1 (zh) * 2020-10-28 2022-05-05 恒元生物医药科技(苏州)有限公司 一种含氮杂环化合物及其应用
CA3200620A1 (en) 2020-12-24 2022-06-30 Xiaohui Gu Aromatic heterocyclic compound, and pharmaceutical composition and application thereof
AU2022254105A1 (en) * 2021-04-10 2023-10-26 Mei Pharma, Inc. Voruciclib dosing regimens and methods of treatment including the same
WO2023014817A1 (en) * 2021-08-03 2023-02-09 Syros Pharmaceuticals, Inc. Compositions and methods for treating lymphomas with a cdk7 inhibitor in combination with a btk inhibitor
WO2023040998A1 (en) * 2021-09-17 2023-03-23 Taizhou Eoc Pharma Co., Ltd. A cyclin-dependent kinase inhibitor
WO2023049691A1 (en) * 2021-09-23 2023-03-30 Zeno Management, Inc. Cdk7 inhibitors and methods of treating cancer
WO2023109876A1 (en) * 2021-12-16 2023-06-22 Edigene Therapeutics (Beijing) Inc. Biomarkers for colorectal cancer treatment
AR128066A1 (es) * 2021-12-22 2024-03-20 Insilico Medicine Ip Ltd Compuesto heterocíclico de pirimidina y método de preparación y uso médico de los mismos
CN114736204A (zh) * 2022-05-06 2022-07-12 湖北工业大学 一种培西达替尼结构类似物的制备方法及其抗肿瘤中的应用
WO2023246371A1 (zh) * 2022-06-24 2023-12-28 中国科学院基础医学与肿瘤研究所(筹) 具有嘧啶并噻吩结构的小分子化合物及其应用
CN117384135A (zh) * 2022-07-04 2024-01-12 浙江同源康医药股份有限公司 用作cdk7激酶抑制剂的化合物及其应用
WO2024097179A1 (en) * 2022-11-02 2024-05-10 Vincerx Pharma, Inc. Combination therapies comprising a cdk9 inhibitor for cancer
CN116082337B (zh) * 2023-03-16 2023-06-23 英矽智能科技(上海)有限公司 炔基取代的杂环化合物，其制法与医药上的用途

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20230210852A1 (en) * 2020-05-29 2023-07-06 Syros Pharmaceuticals, Inc. Methods of treating cancer in patients with an anomalous kras gene or deletions within chromosome 9

Family Cites Families (43)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2319693C9 (ru) 1999-01-13 2008-08-20 Байер Копэрейшн Производные мочевины (варианты), фармацевтическая композиция (варианты) и способ лечения заболевания, связанного с ростом раковых клеток (варианты)
US8124630B2 (en) 1999-01-13 2012-02-28 Bayer Healthcare Llc ω-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
EP1158985B1 (en) 1999-01-13 2011-12-28 Bayer HealthCare LLC OMEGA-CARBOXY ARYL SUBSTITUTED DIPHENYL UREAS AS p38 KINASE INHIBITORS
JP3994262B2 (ja) 1999-10-04 2007-10-17 セイコーエプソン株式会社 半導体装置及びその製造方法、回路基板並びに電子機器
GB0000313D0 (en) 2000-01-10 2000-03-01 Astrazeneca Uk Ltd Formulation
US7235576B1 (en) 2001-01-12 2007-06-26 Bayer Pharmaceuticals Corporation Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
KR20090087139A (ko) 2001-10-30 2009-08-14 노파르티스 아게 Ｆｌｔ３ 수용체 티로신 키나아제 활성의 억제제로서의 스타우로스포린 유도체
SI1478358T1 (sl) 2002-02-11 2013-09-30 Bayer Healthcare Llc Sorafenib tozilat za zdravljenje bolezni, značilnih po abnormalni angiogenezi
GB0308466D0 (en) * 2003-04-11 2003-05-21 Novartis Ag Organic compounds
TWI324604B (en) 2003-06-18 2010-05-11 Novartis Ag New use of staurosporine derivatives
EP1797038B1 (en) 2004-09-29 2012-06-13 Bayer Pharma Aktiengesellschaft Thermodynamically stable form of bay 43-9006 tosylate
WO2006038001A1 (en) * 2004-10-06 2006-04-13 Celltech R & D Limited Aminopyrimidine derivatives as jnk inhibitors
CN102584754B (zh) 2005-03-04 2016-02-03 默沙东公司 具有抗糖尿病活性的稠合芳香化合物
CN101132779B (zh) 2005-03-07 2016-03-16 拜尔健康护理有限责任公司 用于治疗癌症的包含ω-羧芳基取代的二苯基脲的药物组合物
WO2007075869A2 (en) 2005-12-23 2007-07-05 Ariad Pharmaceuticals, Inc. Bicyclic heteroaryl compounds
JP2010526807A (ja) 2007-05-07 2010-08-05 メルク・シャープ・エンド・ドーム・コーポレイション 抗糖尿病活性を有する縮合芳香族化合物を用いた治療法
KR101600634B1 (ko) 2007-12-28 2016-03-07 미쓰비시 타나베 파마 코퍼레이션 항암제
SI2300013T1 (en) * 2008-05-21 2018-03-30 Adriad Pharmacaceuticals, Inc. Phosphorus derivatives as kinase inhibitors
US8546399B2 (en) 2009-05-26 2013-10-01 Abbvie Inc. Apoptosis inducing agents for the treatment of cancer and immune and autoimmune diseases
US8563567B2 (en) 2009-12-30 2013-10-22 Arqule, Inc. Substituted heterocyclic compounds
EP2796456A1 (en) 2010-12-09 2014-10-29 Amgen Inc. Bicyclic compounds as Pim inhibitors
US9539251B2 (en) 2012-09-07 2017-01-10 Genentech, Inc. Combination therapy of a type II anti-CD20 antibody with a selective Bcl-2 inhibitor
US20140296218A1 (en) 2012-10-25 2014-10-02 Whitehead Institute For Biomedical Research Super-enhancers and methods of use thereof
CA3022250A1 (en) 2012-12-12 2014-06-12 Ariad Pharmaceuticals, Inc. Crystalline forms of 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-n-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide mono hydrochloride
WO2014124230A2 (en) 2013-02-08 2014-08-14 Celgene Avilomics Research, Inc. Erk inhibitors and uses thereof
EP3057956B1 (en) * 2013-10-18 2021-05-05 Dana-Farber Cancer Institute, Inc. Polycyclic inhibitors of cyclin-dependent kinase 7 (cdk7)
WO2015058126A1 (en) * 2013-10-18 2015-04-23 Syros Pharmaceuticals, Inc. Heteroaromatic compounds useful for the treatment of prolferative diseases
EP3057954A2 (en) * 2013-10-18 2016-08-24 Syros Pharmaceuticals, Inc. Heteromaromatic compounds useful for the treatment of proliferative diseases
PT3126352T (pt) * 2014-04-04 2018-12-27 Syros Pharmaceuticals Inc Inibidores da quinase dependente de ciclina 7 (cdk7)
WO2015154022A1 (en) * 2014-04-05 2015-10-08 Syros Pharmaceuticals, Inc. Inhibitors of cyclin-dependent kinase 7 (cdk7)
CN111892579B (zh) 2014-06-12 2023-07-25 上海艾力斯医药科技股份有限公司 一类激酶抑制剂
EA034691B1 (ru) 2014-06-19 2020-03-06 Ариад Фармасьютикалз, Инк. Гетероарильные соединения для ингибирования киназ
WO2016058544A1 (en) * 2014-10-16 2016-04-21 Syros Pharmaceuticals, Inc. Inhibitors of cyclin-dependent kinase 7 (cdk7)
JP6861166B2 (ja) 2015-03-27 2021-04-21 ダナ−ファーバー キャンサー インスティテュート， インコーポレイテッド サイクリン依存性キナーゼの阻害剤
SG11201805092WA (en) * 2015-12-23 2018-07-30 Harvard College Cortistatin analogs and uses thereof
BR112019000716A2 (pt) * 2016-07-13 2019-05-07 Syros Pharmaceuticals Inc inibidores de quinase dependente de ciclina (cdk7)
EP3545314A4 (en) 2016-11-28 2020-10-07 Dana-Farber Cancer Institute, Inc. REAGENTS AND METHODS OF ANALYSIS OF PROTEINS AND METABOLITES TARGETED BY COVALENT PROBES
EP3647311B1 (en) 2017-06-30 2023-11-01 Beijing Tide Pharmaceutical Co., Ltd. Rho-associated protein kinase inhibitor, pharmaceutical composition comprising same, and preparation method and use thereof
AU2019209475A1 (en) * 2018-01-16 2020-08-20 Syros Pharmaceuticals, Inc. Inhibitors of cyclin-dependent kinase 7 (CDK7)
AU2019209470A1 (en) 2018-01-16 2020-08-13 Syros Pharmaceuticals, Inc. Inhibitors of cyclin-dependent kinase 7 (CDK7)
WO2019204781A1 (en) 2018-04-20 2019-10-24 Design Therapeutics Inc. Methods and compounds for the treatment of genetic disease
US20210284629A1 (en) 2018-05-09 2021-09-16 Design Therapeutics, Inc. Methods and compounds for the treatment of genetic disease
KR20210118812A (ko) * 2018-11-01 2021-10-01 사이로스 파마수티컬스, 인크. 시클린-의존성 키나제 7 (cdk7)의 억제제

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20230210852A1 (en) * 2020-05-29 2023-07-06 Syros Pharmaceuticals, Inc. Methods of treating cancer in patients with an anomalous kras gene or deletions within chromosome 9

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Lolli et al., Cell Cycle 2005 Apr;4(4):572-7. Epub 2005 Apr 16 (Year: 2005) *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210403495A1 (en) * 2018-11-01 2021-12-30 Syros Pharmaceuticals, Inc. Inhibitors of cyclin-dependent kinase 7 (cdk7)
US11945785B2 (en) 2021-12-30 2024-04-02 Biomea Fusion, Inc. Pyrazine compounds as inhibitors of FLT3

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