WO2022120354A1 - Tead inhibitors and uses thereof - Google Patents

Tead inhibitors and uses thereof Download PDF

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Publication number
WO2022120354A1
WO2022120354A1 PCT/US2021/072684 US2021072684W WO2022120354A1 WO 2022120354 A1 WO2022120354 A1 WO 2022120354A1 US 2021072684 W US2021072684 W US 2021072684W WO 2022120354 A1 WO2022120354 A1 WO 2022120354A1
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increased
cancer
tead
compound
activity
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PCT/US2021/072684
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English (en)
French (fr)
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Alfredo C. Castro
Michael Burke
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Ikena Oncology, Inc.
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Priority to KR1020237021880A priority Critical patent/KR20230131189A/ko
Priority to CN202180091724.XA priority patent/CN117015531A/zh
Priority to JP2023533707A priority patent/JP2023553866A/ja
Priority to CA3200814A priority patent/CA3200814A1/en
Priority to IL303376A priority patent/IL303376A/en
Priority to AU2021392040A priority patent/AU2021392040A1/en
Priority to EP21839798.2A priority patent/EP4255895A1/en
Publication of WO2022120354A1 publication Critical patent/WO2022120354A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • TEAD INHIBITORS AND USES THEREOF SEQUENCE LISTING [0001] The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on November 30, 2021, is named 187446_SL.txt and is 23,551 bytes in size. TECHNICAL FIELD OF THE INVENTION [0002] The present invention relates to compounds and methods useful for inhibition of Transcriptional Enhancer Associate Domain (TEAD). The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of various diseases, disorders, and conditions as described herein.
  • Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are transcriptional co-activators of the Hippo pathway network and regulate cell proliferation, migration, and apoptosis. Inhibition of the Hippo pathway promotes YAP/TAZ translocation to the nucleus, wherein YAP/TAZ interact with TEAD transcription factors and coactivate the expression of target genes and promote cell proliferation. Hyperactivation of YAP and TAZ and/or mutations in one or more members of the Hippo pathway network have been implicated in numerous cancers.
  • SUMMARY OF THE INVENTION [0004] The Hippo signaling cascade is an important pathway for cancer biogenesis and tumor maintenance.
  • the Hippo pathway is heavily mutated across many cancer indications through loss of function mutations in genes such as NF2.
  • These pro-tumor mutations lead to the constitutive activation of the downstream transcriptional coactivators YAP and TAZ that drive the expression of many pro-survival and proliferation genes through the essential interaction with a TEAD protein family member.
  • this unrestrained transcriptional program drives enhanced immune suppression in the tumor microenvironment.
  • novel small molecule inhibitors were identified that selectively bind to TEAD and disrupt their interaction with YAP and TAZ, thereby downregulating YAP- and TAZ-dependent transcription. As demonstrated herein, these TEAD inhibitors prevent TEAD palmitoylation, which is critical for the interaction between YAP and TEAD.
  • the TEAD inhibitors described herein inhibit in vitro proliferation of YAP-dependent (i.e., Hippo pathway-deficient cancer cell lines), but not Hippo pathway wild type cancer cell lines.
  • the TEAD inhibitor compounds of the present invention did not affect survival of a differentiated mouse podocyte cell line or compromise mouse kidney histology.
  • Subsequent experiments in vivo demonstrate the TEAD inhibitors described herein downregulate YAP-dependent genes in human tumor xenografts after oral dosing.
  • the TEAD inhibitors described herein exhibit single agent tumor growth inhibition of human tumor xenografts in mice at well tolerated oral doses.
  • the present invention provides a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein each variable is independently as defined herein and as described in embodiments herein.
  • Compounds of the present invention, and pharmaceutically acceptable salts and compositions thereof are useful for treating a variety of diseases, disorders or conditions associated with TEAD. Such diseases, disorders, or conditions include cellular proliferative disorders (e.g., cancer as described herein).
  • FIGURE 1 depicts a schematic of Hippo pathway signaling.
  • the present invention provides a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein: L 1 is a covalent bound, or a C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -N(R)-, -O-, or -C(O)-; each of which is optionally substituted; , each R 2 is independently selected from -OR, -C(O)NR 2 , optionally substituted -C 1-6 aliphatic, each Y is independently N or CR 5 ; each R 3 is independently H or optionally substituted -C1-6 aliphatic; each R 4 is independently -S(O)2NR2, -S(O)2R, -C(O)NR2, -C(O)R, or optionally substituted -C1-6 aliphatic; each R 5 is independently R, -CN, -C(O)R, -C(O)NR 2
  • aliphatic or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle,” “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule.
  • aliphatic groups contain 1-6 aliphatic carbon atoms.
  • aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms.
  • “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic C3-C6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule.
  • Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
  • the term “bicyclic ring” or “bicyclic ring system” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or having one or more units of unsaturation, having one or more atoms in common between the two rings of the ring system.
  • the term includes any permissible ring fusion, such as ortho-fused or spirocyclic.
  • heterocyclic is a subset of “bicyclic” that requires that one or more heteroatoms are present in one or both rings of the bicycle. Such heteroatoms may be present at ring junctions and are optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc.
  • a bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • bridged bicyclic refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge.
  • a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen).
  • a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted.
  • Exemplary bicyclic rings include: Exemplary bridged bicyclics include: [0013] The term “lower alkyl” refers to a C1-4 straight or branched alkyl group.
  • lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.
  • lower haloalkyl refers to a C 1-4 straight or branched alkyl group that is substituted with one or more halogen atoms.
  • heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl)).
  • unsaturated as used herein, means that a moiety has one or more units of unsaturation.
  • bivalent C 1-8 (or C 1-6 ) saturated or unsaturated, straight or branched, hydrocarbon chain refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.
  • alkylene refers to a bivalent alkyl group.
  • An “alkylene chain” is a polymethylene group, i.e., –(CH2)n–, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3.
  • a substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
  • alkenylene refers to a bivalent alkenyl group.
  • a substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
  • cyclopropylenyl refers to a bivalent cyclopropyl group of the following structure: .
  • halogen means F, Cl, Br, or I.
  • aryl used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members.
  • aryl may be used interchangeably with the term “aryl ring.”
  • aryl refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents.
  • aryl is a group in which an aromatic ring is fused to one or more non–aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.
  • heteroaryl and “heteroar—,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 ⁇ electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms.
  • heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
  • Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl.
  • heteroaryl and “heteroar—”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring.
  • Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H–quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3–b]–1,4–oxazin–3(4H)–one.
  • heteroaryl group may be mono– or bicyclic.
  • heteroaryl may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted.
  • heteroarylkyl refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.
  • heterocycle As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5– to 7–membered monocyclic or 7–10–membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above.
  • nitrogen includes a substituted nitrogen.
  • the nitrogen may be N (as in 3,4–dihydro– 2H–pyrrolyl), NH (as in pyrrolidinyl), or + NR (as in N–substituted pyrrolidinyl).
  • a heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.
  • saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl.
  • heterocycle used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H–indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl.
  • a heterocyclyl group may be mono– or bicyclic.
  • heterocyclylalkyl refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.
  • partially unsaturated refers to a ring moiety that includes at least one double or triple bond.
  • partially unsaturated is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.
  • compounds of the invention may contain “optionally substituted” moieties.
  • substituted means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
  • an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
  • R * is C1–6 aliphatic
  • R * is optionally substituted with halogen, – R ⁇ , -(haloR ⁇ ), -OH, –OR ⁇ , –O(haloR ⁇ ), –CN, –C(O)OH, –C(O)O R ⁇ , –NH 2 , –NHR ⁇ , –NR ⁇ 2 , or – NO 2
  • each R ⁇ is independently selected from C 1–4 aliphatic, –CH 2 Ph, –O(CH 2 ) 0–1 Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R ⁇ is unsubstituted or where preceded by halo is substituted only with one or more halogens.
  • An optional substituent on a substitutable nitrogen is independently –R ⁇ , –NR ⁇ 2 , – C(O)R ⁇ , –C(O)OR ⁇ , –C(O)C(O)R ⁇ , –C(O)CH2C(O)R ⁇ , -S(O)2R ⁇ , -S(O)2NR ⁇ 2, –C(S)NR ⁇ 2, – C(NH)NR ⁇ 2, or –N(R ⁇ )S(O)2R ⁇ ; wherein each R ⁇ is independently hydrogen, C1–6 aliphatic, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, two independent occurrences of R ⁇ , taken together with their intervening atom(s) form an unsubstitute
  • the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of 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 used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art 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, malate, 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 + (C1–4alkyl)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, loweralkyl sulfonate and aryl sulfonate.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.
  • a warhead moiety of a provided compound comprises one or more deuterium atoms.
  • inhibitor or “TEAD inhibitor” or “TEAD antagonist” are defined as a compound that binds to and/or inhibits TEAD with measurable affinity. In some embodiments, inhibition in the presence of the inhibitor is observed in a dose-dependent manner.
  • the measured signal (e.g., signaling activity or biological activity) is at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% lower than the signal measured with a negative control under comparable conditions.
  • an inhibitor has an IC50 and/or binding constant of less than about 100 ⁇ M, less than about 50 ⁇ M, less than about 1 ⁇ M, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.
  • measurable affinity and “measurably inhibit,” as used herein, means a measurable change or inhibition in TEAD activity between a sample comprising a compound of the present invention, or composition thereof, and TEAD, and an equivalent sample comprising TEAD, in the absence of said compound, or composition thereof.
  • the present invention provides a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein: L 1 is a covalent bound, or a C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -N(R)-, -O-, or -C(O)-; each of which is optionally substituted;
  • each R w is independently selected from each R 2 is independently selected from -OR, -C(O)NR 2 , optionally substituted -C 1-6 aliphatic, each Y is independently N or CR 5 ; each R 3 is independently H or optionally substituted -C1-6 aliphatic; each R 4 is independently -S(O)2NR2, -S(O)2R, -C(O)NR2, -C(O)R, or optionally substituted -C1-6 aliphatic; each R 5 is independently R, -CN, -C(O)R, -C(O)NR2, or optionally substituted 5-6 membered heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each m is independently 0, 1, or 2; p is 0, 1, or 2, and each R is independently H, optionally substituted -C1-6 aliphatic, optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclyl, or optionally substituted 3-8 membere
  • L 1 is a covalent bound, or a C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -N(R)-, -O-, or -C(O)-.
  • L 1 is a covalent bond.
  • L 1 is C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with - N(R)-.
  • L 1 is C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O- .
  • L 1 is C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with - C(O)-.
  • L 1 is -NH-.
  • L 1 is -NH-CH 2 -.
  • L 1 is -NH-CH2-CH2-.
  • L 1 is –CH2-.
  • L 1 is .
  • Ring A is optionally substituted .
  • Ring A is optionally substituted .
  • Ring A is optionally substituted .
  • Ring A is optionally substituted .
  • Ring A is optionally substituted .
  • Ring A is optionally substituted .
  • Ring A is optionally substituted .
  • Ring A is optionally substituted .
  • Ring A is optionally substituted .
  • Ring A is optionally substituted .
  • Ring A is optionally substituted .
  • Ring A is optionally substituted .
  • Ring A is optionally substituted .
  • Ring A is selected from , , , , , wherein each R 1 is independently R, halogen, -CN, -C(O)R, -C(O)NR2, -OR, -SR, -S(O)2NR2, or -S(O)2R, and each n is independently 0, 1, 2, or 3, wherein each R is independently as defined herein and as described in embodiments herein.
  • R 1 is R.
  • R 1 is halogen.
  • R 1 is -CN.
  • R 1 is -C(O)R.
  • R 1 is - C(O)NR 2 .
  • R 1 is -OR. In some embodiments, R 1 is -SR. In some embodiments, R 1 is -S(O)2NR2. In some embodiments, R 1 is -S(O)2R. [0061] In some embodiments, each R 1 is independently H, halogen, -C1-6 aliphatic optionally substituted by 1-6 halogen, 3-8 membered saturated or partially unsaturated monocyclic carbocyclyl optionally substituted by 1-6 halogen, or 3-8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur optionally substituted by 1-6 halogen.
  • each R 1 is independently H, -CF 3 , -C(O)NH 2 , -CH 3 , -CH 2 CH 3 , -OCH3, -CHF2, -OCF3, -OCHF2, -SCF3, -Cl, -S(O)2-NH2, -OCH2CH3, -F, -C(O)NHCH3, -CN, - [0063]
  • each R 1 is independently selected from those depicted in Table 1, below.
  • n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.
  • Ring A is selected from , wherein each of R 1 is as defined above and described in embodiments herein, both singly and in combination. [0066] In some embodiments, Ring A is selected from , , and , wherein each R 1 is as defined above and described in embodiments herein, both singly and in combination.
  • Ring A is selected from those depicted in Table 1, below. wherein each of R 2 , R 3 , R w , p, and R 4 is as defined herein and described in embodiments herein, both singly and in combination. [0071] In some embodiments, Ring wherei 2 w n each of R and R is as defined herein and described in embodiments herein, both singly and in combination. [0072] In some embodiments, Ring 4 w wherein each of R and R is as defined herein and described in embodiments herein, both singly and in combination. [0073] In some embodiments, Ring , wherein each of R 2 and R w is as defined herein and described in embodiments herein, both singly and in combination.
  • Ring wherein each of R 2 and R w is as defined herein and described in embodiments herein, both singly and in combination.
  • Ring B is , wherein each of R 4 and R w is as defined herein and described in embodiments herein, both singly and in combination.
  • Ring wherein each of R 2 and R w is as defined herein and described in embodiments herein, both singly and in combination.
  • Ring 3 wherein each of R and p is as defined herein and described in embodiments herein, both singly and in combination.
  • Ring B is , wherein R w is as defined herein and described in embodiments herein. In some embodiments, Ring B is , wherein R w is as defined herein and described in embodiments herein. [0079] In some embodiments, Ring B is selected from those depicted in Table 1, below. [0080] As defined generally above, R w is selected from . [0081] In some embodiments, R w is . In some embodiments, . some embodiments, R w is . In some embodiments, R w . In some [0082] In some embodiments, R w is selected from those depicted in Table 1, below.
  • each R 2 is independently selected from -OR, -C(O)NR2, optionally substituted -C 1-6 aliphatic, , , , , , wherein each of Y, m, and R 5 is as defined herein and described in embodiments herein, both singly and in combination..
  • R 2 is -OR.
  • R 2 is -C(O)NR 2 .
  • R 2 is optionally substituted -C1-6 aliphatic.
  • R 2 is . In some embodiments, .
  • R 2 some embodiments, some embodiments, R 2 is . In some embodiments, R 2 is . In some embodiments, R 2 is . In some embodiments, . In some embodiments, some embodiments, some embodiments, some embodiments, some embodiments, some embodiments, R 2 is .
  • R 2 is selected from those depicted in Table 1, below.
  • each Y is independently N or CR 5 .
  • Y is N.
  • Y is CR 5 .
  • Y is CH.
  • both Y are N.
  • both Y are CR 5 .
  • one Y is N, and the other Y is CR 5 .
  • both Y are CH.
  • one Y is N, and the other Y is CH.
  • Y is selected from those depicted in Table 1, below.
  • each R 3 is independently H, -C(O)R, or optionally substituted -C1-6 aliphatic, wherein R is as defined herein and described in embodiments herein.
  • R 3 is H.
  • R 3 is -C(O)R.
  • R 3 is optionally substituted -C 1-6 aliphatic.
  • R 3 is selected from H, -CH3, -CH2CH3, -C(O)CH3, and .
  • R 3 is selected from those depicted in Table 1, below.
  • each R 4 is independently -S(O) 2 NR 2 , -S(O) 2 R, -C(O)NR 2 , -C(O)R, or optionally substituted -C1-6 aliphatic, wherein each R is independently as defined herein and as described in embodiments herein.
  • R 4 is -S(O) 2 NR 2 .
  • R 4 is -S(O)2R.
  • R 4 is -C(O)NR2.
  • R 4 is -C(O)R.
  • R 4 is -optionally substituted -C 1-6 aliphatic. [00106] In some embodiments, R 4 is selected from: . [00107] In some embodiments, R 4 is selected from those depicted in Table 1, below. [00108] As defined generally above, each R 5 is independently R, -CN, -C(O)R, -C(O)NR 2 , or optionally substituted 5-6 membered heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each R is independently as defined herein and as described in embodiments herein. [00109] In some embodiments, R 5 is R. [00110] In some embodiments, R 5 is -CN.
  • R 5 is -C(O)R. [00112] In some embodiments, R 5 is -C(O)NR 2 . [00113] In some embodiments, R 5 is optionally substituted 5-6 membered heteroaryl having 1- 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00114] In some embodiments, each R 5 is independently selected from: H, -CH 3 , -CD 3 , [00115] In some embodiments, each R 5 is independently selected from: -CH 3 , -CH 2 CH 2 OCH 3 , [00116] In some embodiments, R 5 is selected from those depicted in Table 1, below. [00117] As defined generally above, each m is independently 0, 1, or 2.
  • m is 0. In some embodiments, m is 1. In some embodiments, m is 2. [00119] In some embodiments, m is selected from those depicted in Table 1, below. [00120] As defined generally above, p is 0, 1, or 2. [00121] In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. [00122] In some embodiments, p is selected from those depicted in Table 1, below.
  • each R is independently H, optionally substituted -C1-6 aliphatic, optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclyl, or optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R is H.
  • R is optionally substituted -C 1-6 aliphatic.
  • R is unsubstituted -C1-6 aliphatic.
  • R is -C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO2.
  • R is -C1-6 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F. In some embodiments, R is -C 1-3 aliphatic substituted 1, 2, 3, 4, 5, or 6 times by –F. In some embodiments, R is –CH3. In some embodiments, R is –CH2CH3. In some embodiments, R is –CF3. In some embodiments, R is –CHF2. [00126] In some embodiments, R is optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R is unsubstituted 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic carbocyclyl.
  • R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic carbocyclyl substituted 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, –NO 2 , or -C 1-6 aliphatic, wherein the -C 1-6 aliphatic is optionally substituted 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO2.
  • R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic carbocyclyl substituted 1, 2, 3, 4, 5, or 6 times by –halogen.
  • R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic carbocyclyl substituted 1, 2, 3, 4, 5, or 6 times by -C 1-6 aliphatic, wherein the -C 1-6 aliphatic is optionally substituted 1, 2, 3, 4, 5, or 6 times by -halogen.
  • R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic carbocyclyl substituted 1, 2, 3, 4, 5, or 6 times by –F.
  • R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic carbocyclyl substituted 1, 2, 3, 4, 5, or 6 times by -C1-6 aliphatic, wherein the -C1-6 aliphatic is optionally substituted 1, 2, 3, 4, 5, or 6 times by -F.
  • R is optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R is unsubstituted 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which is substituted 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, –NO 2 , or -C 1-6 aliphatic, wherein the -C 1-6 aliphatic is optionally substituted 1, 2, 3, 4, 5, or 6 times by -halogen, -CN, or –NO2.
  • R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur substituted 1, 2, 3, 4, 5, or 6 times by –halogen.
  • R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur substituted 1, 2, 3, 4, 5, or 6 times by -C1-6 aliphatic, wherein the -C1-6 aliphatic is optionally substituted 1, 2, 3, 4, 5, or 6 times by -halogen.
  • R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur substituted 1, 2, 3, 4, 5, or 6 times by –F.
  • R is 3, 4, 5, 6, 7, or 8 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur substituted 1, 2, 3, 4, 5, or 6 times by -C1-6 aliphatic, wherein the -C1-6 aliphatic is optionally substituted 1, 2, 3, 4, 5, or 6 times by -F.
  • R is selected from those depicted in Table 1, below. [00130] In some embodiments, the present invention provides a compound of Formulas:
  • each of R 1 , L 1 , R w , Y, m, n, and R 5 is as defined above and as described in embodiments herein, both singly and in combination.
  • the present invention provides a compound of Formulas:
  • the present invention provides a compound of Formulas: , , IV-a IV-b
  • each of R 1 , L 1 , R w , n, and R 5 is as defined above and as described in embodiments herein, both singly and in combination.
  • the present invention provides a compound of Formulas:
  • V-m V-n V-o or a pharmaceutically acceptable salt thereof, wherein each of R 1 , R w , L 1 , and R 5 is as defined above and as described in embodiments herein, both singly and in combination.
  • the present invention provides a compound of Formulas: ,
  • the present invention provides a compound of Formulas: , , , , , VII-i VII-j
  • the present invention provides a compound of Formulas: , , VIII-g VIII-h or a pharmaceutically acceptable salt thereof, wherein each of R 1 , L 1 , R w , and n is as defined above and as described in embodiments herein, both singly and in combination.
  • the present invention provides a compound of Formulas: , , VIII-g VIII-h or a pharmaceutically acceptable salt thereof, wherein each of R 1 , L 1 , R w , and n is as defined above and as described in embodiments herein, both singly and in combination.
  • the present invention provides a compound of Formulas:
  • IX-s IX-t or a pharmaceutically acceptable salt thereof, wherein each of R 1 , L 1 , R w , Y, m, n, and R 5 is as defined above and as described in embodiments herein, both singly and in combination.
  • the present invention provides a compound of Formulas: , ,
  • each of R 1 , L 1 , R w , Y, n, and R 5 is as defined above and as described in embodiments herein, both singly and in combination.
  • the present invention provides a compound of Formulas:
  • the present invention provides a compound of Formulas: XII-a XII-b XII-c
  • the compounds provided herein are capable of covalently binding to an amino acid residue (such as cysteine, lysine, histidine, or other residues capable of being covalently modified) present in the binding pocket of a target protein, for example, TEAD, thereby irreversibly inhibiting the protein.
  • a warhead group is capable of covalently binding to cysteine.
  • a warhead group is capable of covalently binding to serine.
  • a warhead group is capable of covalently binding to lysine. In some embodiments, a warhead group is capable of covalently binding to Cys359 of hTEAD1, Cys405 of hTEAD1, Cys380 of hTEAD2, Cys368 of hTEAD3, and/or Cys367 of hTEAD4. In some embodiments, a warhead group is capable of covalently binding to Ser356 of hTEAD1, Ser345 and/or Ser377 of hTEAD2, Ser365 of hTEAD3, and/or Ser364 of hTEAD4.
  • a warhead group is capable of covalently binding to Lys336 of hTEAD1, Lys357 of hTEAD2, Lys345 of hTEAD3, and/or Lys344 of hTEAD4.
  • Representative reference amino acid sequences of human TEAD1, human TEAD2, human TEAD3, and human TEAD4 include UniProt KB ID P28347-1 (SEQ ID NO: 1), UniProtKB ID Q15562 (SEQ ID NO: 2), UniProtKB ID Q99594 (SEQ ID NO: 3), and UniProtKB ID Q15561 (SEQ ID NO: 4), respectively.
  • TEAD coactivator binding domains which is shown in Table 1 of “Targeting Transcriptional Enhanced Associate Domains (TEADs),” J. Med. Chem.2018, 61, 5057-5072, the entire content of which is incorporated herein by reference.
  • the present invention provides a compound set forth in Table 1, above, or a pharmaceutically acceptable salt thereof.
  • a compound of the present invention is not a compound selected from: [00145]
  • the compounds of this invention can be prepared or isolated in general by synthetic and/or semi-synthetic methods known to those skilled in the art for analogous compounds and by methods described in detail in the Examples, herein.
  • the present invention provides an intermediate compound described in the Examples, or a salt thereof. 4.
  • Pharmaceutically acceptable compositions [00146] According to another embodiment, the invention provides a pharmaceutical composition comprising a compound of this invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the amount of compound in compositions of this invention is such that is effective to measurably inhibit TEAD, or a variant or mutant thereof, in a biological sample or in a patient. In certain embodiments, the amount of compound in compositions of this invention is such that is effective to measurably inhibit TEAD, or a variant or mutant thereof, in a biological sample or in a patient. In certain embodiments, a composition of this invention is formulated for administration to a patient in need of such composition. In some embodiments, a composition of this invention is formulated for oral administration to a patient. [00147]
  • patient or “subject” as used herein, means an animal, preferably a mammal, and most preferably a human.
  • compositions of this invention refers to a non- toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated.
  • Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention 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- polyoxypropy
  • a “pharmaceutically acceptable derivative” means any non-toxic salt, ester, salt of an ester or other derivative of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof.
  • the term "inhibitorily active metabolite or residue thereof” means that a metabolite or residue thereof is also an inhibitor of TEAD, or a variant or mutant thereof.
  • Compositions of the present invention canbe administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • compositions of this invention cancan be aqueous or oleaginous suspension. These suspensions cancan be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation cancan 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 can be employed are water, Ringer’s solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or di- glycerides.
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions can also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • a long-chain alcohol diluent or dispersant such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • Other commonly used surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms can also be used for the purposes of formulation.
  • compositions of this invention can be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • carriers commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents can also be added.
  • pharmaceutically acceptable compositions of this invention can be administered in the form of suppositories for rectal administration.
  • compositions of this invention can also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
  • Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches can also be used.
  • compositions can be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • provided pharmaceutically acceptable compositions can be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride.
  • the pharmaceutically acceptable compositions can be formulated in an ointment such as petrolatum.
  • compositions of this invention can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well- known in the art of pharmaceutical formulation and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents. [00160] Most preferably, pharmaceutically acceptable compositions of this invention are formulated for oral administration. Such formulations can be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this invention are administered without food. In other embodiments, pharmaceutically acceptable compositions of this invention are administered with food.
  • compositions of the present invention that can be combined with the carrier materials to produce a composition in a single dosage form varies depending upon the host treated, the particular mode of administration.
  • provided compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions.
  • a specific dosage and treatment regimen for any particular patient depends upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
  • the amount of a compound of the present invention in the composition also depends upon the particular compound in the composition.
  • Uses of Compounds and Pharmaceutically Acceptable Compositions The Hippo Signaling Network [00163]
  • the Hippo signaling network (also known as the Salvador/Warts/Hippo (SWH) pathway) is a master regulator of cell proliferation, death, and differentiation.
  • the main function of the Hippo signaling pathway is to regulate negatively the transcriptional co-activators Yes-associated protein (YAP) and its paralogue, the transcriptional co-activator with PDZ-binding motif (TAZ; also known as WWTR1).
  • YAP transcriptional co-activators Yes-associated protein
  • TEZ transcriptional co-activator with PDZ-binding motif
  • the Hippo kinase cascade phosphorylates and inhibits YAP/TAZ by promoting its cytoplasmic retention and degradation, thereby inhibiting the growth promoting function regulated under the YAP/TAZ control.
  • YAP also known as YAP1 or YAP65
  • TAZ TEAD family of transcription factors to upregulate genes that promote proliferation and migration, and inhibit apoptosis.
  • unregulated upregulation of these genes involved in proliferation, migration, and anti- apoptosis leads to development of cancer.
  • overexpression of YAP/TAZ is associated with cancer.
  • Additional core members of the Hippo signaling pathway comprise the serine/threonine kinases MST1/2 (homologues of Hippo/Hpo in Drosophila), Lats1/2 (homologues of Warts/Wts), and their adaptor proteins Sav1 (homologue of Salvador/Sav) and Mob (MOBKL1A and MOBKL1B; homologues of Mats), respectively.
  • MST1/2 kinase complexes with the scaffold protein Sav1, which in turn phosphorylates and activates Lats1/2 kinase.
  • Lats1/2 is also activated by the scaffold protein Mob.
  • Lats1/2 phosphorylates YAP at the [HXRXXS] (SEQ ID NO: 9) consensus motifs.
  • YAP comprises five [HXRXXS] (SEQ ID NO: 9) consensus motifs, wherein X denotes any amino acid residue.
  • Lats1/2 phosphorylates YAP at one or more of the consensus motifs.
  • Lats1/2 phosphorylates YAP at all five of the consensus motifs.
  • Lats1/2 phosphorylate at the S127 amino acid position.
  • the phosphorylation of YAP S127 promotes 14-3-3 protein binding and results in cytoplasmic sequestration of YAP. Mutation of YAP at the S127 position thereby disrupts its interaction with 14-3-3 and subsequently promotes nuclear translocation.
  • Additional phosphorylation occurs at the S381 amino acid position in YAP. Phosphorylation of YAP at the S381 position and on the corresponding site in TAZ primes both proteins for further phosphorylation events by CK1 ⁇ / ⁇ in the degradation motif, which then signals for interaction with the ⁇ -TRCP E3 ubiquitin ligase, leading to polyubiquitination and degradation of YAP.
  • Lats1/2 phosphorylates TAZ at the [HXRXXS] (SEQ ID NO: 9) consensus motifs.
  • TAZ comprises four [HXRXXS] (SEQ ID NO: 9) consensus motifs, wherein X denotes any amino acid residues.
  • Lats1/2 phosphorylates TAZ at one or more of the consensus motifs.
  • Lats1/2 phosphorylates TAZ at all four of the consensus motifs.
  • Lats1/2 phosphorylate at the S89 amino acid position. The phosphorylation of TAZ S89 promotes 14-3-3 protein binding and results in cytoplasmic sequestration of TAZ.
  • the Skp, Cullin, F-box containing complex is a multi-protein E3 ubiquitin ligase complex that comprises a F-box family member protein (e.g., Cdc4), Skp1, a bridging protein, and RBX1, which contains a small RING Finger domain which interacts with E2 -ubiquitin conjugating enzyme.
  • F-box family member protein e.g., Cdc4
  • Skp1 a bridging protein
  • RBX1 which contains a small RING Finger domain which interacts with E2 -ubiquitin conjugating enzyme.
  • the F-box family comprises more than 40 members, in which exemplary members include F-box/WD repeat-containing protein 1A (FBXW1A, ⁇ TrCP1, Fbxwl, hsSlimb, plkappaBalpha-E3 receptor subunit) and S-phase kinase-associated proteins 2 (SKP2).
  • the SCF complex e.g., SCF ⁇ TrCP1
  • E1 ubiquitin-activating enzyme and an E2 ubiquitin-conjugating enzyme to catalyze the transfer of ubiquitin to the YAP/TAZ substrate.
  • Exemplary E1 ubiquitin-activating enzymes include those encoded by the following genes: UBA1, UBA2, UBA3, UBA5, UBA5, UBA7, ATG7, NAE1, and SAE1.
  • Exemplary E2 ubiquitin-conjugating enzymes include those encoded by the following genes: UBE2A, UBE2B, UBE2C, UBE2D1, UBE2D2, UBE2D3, UBE2E1, UBE2E2, UBE2E3, UBE2F, UBE2G1, UBE2G2, UBE2H, UBE2I, UBE2J1, UBE2J2, UBE2K, UBE2L3, UBE2L6, UBE2M, UBE2N, UBE20, UBE2Q1, UBE2Q2, UBE2R1, UBE2R2, UBE2S, UBE2T, UBE2U, UBE2V1, UBE2V2, UBE2Z, ATG2, BIRC5, and UFC1.
  • the ubiquitinated YAP/TAZ further undergoes the degradation process through the 26S proteasome.
  • the Hippo pathway is regulated upstream by several different families of regulators. In some instances, the Hippo pathway is regulated by the G-protein and its coupled receptors, the Crumbs complex, regulators upstream of the MST kinases, and the adherens junction.
  • YAP/TAZ Interaction with TEAD [00170] In some embodiments, un-phosphorylated and/or dephosphorylated YAP/TAZ accumulates in the nucleus.
  • YAP/TAZ interacts with the TEAD family of transcription factors (e.g., human TEAD1 (UniProt KB ID P28347-1 (SEQ ID NO: 1)), human TEAD2 (UniProtKB ID Q15562 (SEQ ID NO: 2)), human TEAD3 (UniProtKB ID Q99594 (SEQ ID NO: 3)), and human TEAD4 (UniProtKB ID Q15561 (SEQ ID NO: 4)) to activate genes involved in anti-apoptosis and proliferation, such as, for example, CTFG, Cyr61, and FGF1.
  • TEAD1 UniProt KB ID P28347-1 (SEQ ID NO: 1)
  • human TEAD2 UniProtKB ID Q15562 (SEQ ID NO: 2)
  • human TEAD3 UniProtKB ID Q99594 (SEQ ID NO: 3)
  • human TEAD4 UniProtKB ID Q15561 (SEQ ID NO: 4)
  • TEAD TEAD
  • C327S and C359S Three cysteine residues were found that are evolutionarily conserved and mutated to serine in human TEAD1 (C53S, C327S and C359S) to test whether the mutation affects TEAD1 palmitoylation.
  • C53S, C327S and C359S Three cysteine residues were found that are evolutionarily conserved and mutated to serine in human TEAD1 (C53S, C327S and C359S) to test whether the mutation affects TEAD1 palmitoylation.
  • C359S mutant showed the greatest loss of palmitoylation, and C327S and C53S also showed decreased palmitoylation.
  • the compounds disclosed herein modulate the interaction between YAP/TAZ and TEAD. In some embodiments, the compounds disclosed herein bind to TEAD, YAP, or TAZ and prevent the interaction between YAP/TAZ and TEAD. [00173] In some embodiments, the compounds described herein irreversibly inhibit a TEAD transcription factor. In some embodiments, the transcription factor is TEAD1. In some embodiments, the transcription factor is TEAD2. In some embodiments, the transcription factor is TEAD3. In some embodiments, the transcription factor is TEAD4.
  • the compounds described herein covalently bind to the TEAD transcription factor (e.g., TEAD1, TEAD2, TEAD3, or TEAD4). In some embodiments, the compounds described herein irreversibly inhibit the activity of a TEAD transcription factor (e.g., TEAD1, TEAD2, TEAD3, or TEAD4). In some embodiments, the compounds described herein covalently inhibit the activity of a TEAD transcription factor (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4). [00174] In some embodiments, the compounds disclosed herein bind to TEAD1 and disrupt or inhibit the interaction between YAP and TEAD1.
  • the compounds disclosed herein bind to TEAD2 and disrupt or inhibit the interaction between YAP and TEAD2. In some embodiments, the compounds disclosed herein bind to TEAD3 and disrupt or inhibit the interaction between YAP and TEAD3. In some embodiments, the compounds disclosed herein bind to TEAD4 and disrupt or inhibit the interaction between YAP and TEAD4. [00175] In some embodiments, the compounds disclosed herein bind to TEAD1 and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 at C359, and disrupt or inhibit the interaction between YAP and TEAD1.
  • the compounds disclosed herein bind to TEAD1 at C53, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 at C327, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 at C405, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 at C359 and C327, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 at C359 and C53, and disrupt or inhibit the interaction between YAP and TEAD1.
  • the compounds disclosed herein bind to TEAD1 at C53 and C327, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 at C359 and C405, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 at C53 and C405, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 at C327 and C405, and disrupt or inhibit the interaction between YAP and TEAD1.
  • the compounds disclosed herein bind to TEAD1 at C359, C327, and C53, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 at C359, C327, and C405, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 at C359, C353, and C405, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 at C327, C53, and C405, and disrupt or inhibit the interaction between YAP and TEAD1.
  • the compounds disclosed herein bind to TEAD1 at C359, C327, C53, and C405, and disrupt or inhibit the interaction between YAP and TEAD1. [00176] In some embodiments, the compounds disclosed herein bind to TEAD, prevent TEAD palmitoylation, and disrupt or inhibit the interaction between YAP and TEAD. In some embodiments, the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation. In some embodiments, the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359. In some embodiments, the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C53.
  • the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C327. In some embodiments, the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C405. In some embodiments, the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359 and C327. In some embodiments, the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359 and C53. In some embodiments, the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C53 and C327.
  • the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359 and C405. In some embodiments, the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C53 and C405. In some embodiments, the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C327 and C405. In some embodiments, the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359, C327, and C53. In some embodiments, the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359, C327, and C405.
  • the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359, C353, and C405. In some embodiments, the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C327, C53, and C405. In some embodiments, the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359, C327, C53, and C405. [00177] In some embodiments, the compounds disclosed herein bind to TEAD1, prevent TEAD1 palmitoylation, and disrupt or inhibit the interaction between YAP and TEAD1.
  • the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C53, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C327, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C405, and disrupt or inhibit the interaction between YAP and TEAD1.
  • the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359 and C327, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359 and C53, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C53 and C327, and disrupt or inhibit the interaction between YAP and TEAD1.
  • the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359 and C405, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C53 and C405, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C327 and C405, and disrupt or inhibit the interaction between YAP and TEAD1.
  • the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359, C327, and C53, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359, C327, and C405, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359, C353, and C405, and disrupt or inhibit the interaction between YAP and TEAD1.
  • the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C327, C53, and C405, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359, C327, C53, and C405, and disrupt or inhibit the interaction between YAP and TEAD1. [00178] In some embodiments, the compounds disclosed herein bind to TEAD2 at C380, and disrupt or inhibit the interaction between YAP and TEAD2. [00179] In some embodiments, the compounds disclosed herein bind to TEAD2 and prevent TEAD2 palmitoylation.
  • the compounds disclosed herein bind to TEAD2 and prevent TEAD2 palmitoylation at C380. [00180] In some embodiments, the compounds disclosed herein bind to TEAD2, prevent TEAD2 palmitoylation, and disrupt or inhibit the interaction between YAP and TEAD2. In some embodiments, the compounds disclosed herein bind to TEAD2 and prevent TEAD2 palmitoylation at C380, and disrupt or inhibit the interaction between YAP and TEAD2. [00181] In some embodiments, the compounds disclosed herein bind to TEAD3 at C371, and disrupt or inhibit the interaction between YAP and TEAD3. In some embodiments, the compounds disclosed herein bind to TEAD3 at C368, and disrupt or inhibit the interaction between YAP and TEAD3.
  • the compounds disclosed herein bind to TEAD3 at C371 and C368, and disrupt or inhibit the interaction between YAP and TEAD3. [00182] In some embodiments, the compounds disclosed herein bind to TEAD3 and prevent TEAD3 palmitoylation. In some embodiments, the compounds disclosed herein bind to TEAD3 and prevent TEAD3 palmitoylation at C371. In some embodiments, the compounds disclosed herein bind to TEAD3 and prevent TEAD3 palmitoylation at C368. In some embodiments, the compounds disclosed herein bind to TEAD3 and prevent TEAD3 palmitoylation at C368 and C371.
  • the compounds disclosed herein bind to TEAD3, prevent TEAD3 palmitoylation, and disrupt or inhibit the interaction between YAP and TEAD3. In some embodiments, the compounds disclosed herein bind to TEAD3 and prevent TEAD3 palmitoylation at C371, and disrupt or inhibit the interaction between YAP and TEAD3. In some embodiments, the compounds disclosed herein bind to TEAD3 and prevent TEAD3 palmitoylation at C368, and disrupt or inhibit the interaction between YAP and TEAD3. In some embodiments, the compounds disclosed herein bind to TEAD3 and prevent TEAD3 palmitoylation at C371 and C368, and disrupt or inhibit the interaction between YAP and TEAD3.
  • the compounds disclosed herein bind to TEAD4 at C367, and disrupt or inhibit the interaction between YAP and TEAD4. [00185] In some embodiments, the compounds disclosed herein bind to TEAD4 and prevent TEAD4 palmitoylation. In some embodiments, the compounds disclosed herein bind to TEAD4and prevent TEAD4 palmitoylation at C367. [00186] In some embodiments, the compounds disclosed herein bind to TEAD4, prevent TEAD4 palmitoylation, and disrupt or inhibit the interaction between YAP and TEAD4. In some embodiments, the compounds disclosed herein bind to TEAD4 and prevent TEAD4 palmitoylation at C367, and disrupt or inhibit the interaction between YAP and TEAD4.
  • the Hippo pathway is regulated by the G protein-coupled receptor (GPCR) and G protein (also known as guanine nucleotide-binding proteins) family of proteins.
  • G proteins are molecular switches that transmit extracellular stimuli into the cell through GPCRs.
  • monomeric small GTPases and heterotrimeric G protein complexes.
  • the latter class of complexes comprise of alpha (G ⁇ ), beta (G ⁇ ), and gamma (G ⁇ ) subunits.
  • G ⁇ subunits there are several classes of G ⁇ subunits: Gq/11 ⁇ , G12/13 ⁇ , Gi/o ⁇ (G inhibitory, G other), and Gs ⁇ (G stimulatory).
  • Gi ⁇ G inhibitory
  • Go ⁇ G other
  • Gq/11 ⁇ G12/13 ⁇ coupled GPCRs activate YAP/TAZ and promote nuclear translocation.
  • G s ⁇ G stimulatory coupled GPCRs suppress YAP/TAZ activity, leading to YAP/TAZ degradation.
  • G i ⁇ G inhibitory
  • G o ⁇ G other
  • G q/11 ⁇ G 12/13 ⁇ coupled GPCRs activate YAP/TAZ through repression of Lats1/2 activities.
  • Gs ⁇ in some embodiments, induces Lats1/2 activity, thereby promoting YAP/TAZ degradation.
  • G q Family Gq ⁇ (also known as Gq/11 protein), participates in the inositol trisphosphate (IP3) signal transduction pathway and calcium (Ca 2+ ) release from intracellular storage through the activation of phospholipase C (PLC).
  • IP3 inositol trisphosphate
  • Ca 2+ calcium release from intracellular storage through the activation of phospholipase C
  • the activated PLC hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) to diacyl glycerol (DAG) and IP3.
  • IP3 then diffuses through the cytoplasm into the ER or the sarcoplasmic reticulum (SR) in the case of muscle cells, and then binds to inositol trisphosphate receptor (InsP3R), which is a Ca 2+ channel.
  • the binding triggers the opening of the Ca 2+ channel, and thereby increases the release of Ca 2+ into the cytoplasm.
  • the GPCRs that interact with Gq ⁇ include, but are not limited to, 5-hydroxytryptamine receptor (5-HT receptor) types 5-HT 2 and 5-HT 3 ; alpha-1 adrenergic receptor; vasopressin type 1 receptors 1A and 1B; angiotensin II receptor type 1; calcitonin receptor; histamine H1 receptor; metabotropic glutamate receptor, group I; muscarinic receptors M 1 , M 3 , and M 5 ; and trace amine-associated receptor 1.
  • 5-HT receptor 5-hydroxytryptamine receptor
  • alpha-1 adrenergic receptor alpha-1 adrenergic receptor
  • vasopressin type 1 receptors 1A and 1B angiotensin II receptor type 1
  • calcitonin receptor histamine H1 receptor
  • metabotropic glutamate receptor group I
  • muscarinic receptors M 1 , M 3 , and M 5 and trace amine-associated receptor 1.
  • Gq ⁇ there are several types of Gq
  • Gq/11 is encoded by GNA11.
  • Gq/14 is encoded by GNA14.
  • Gq/15 is encoded by GNA15.
  • mutations or modifications of the G q ⁇ genes have been associated with cancer. Indeed, studies have shown that mutations in Gq ⁇ promote uveal melanoma (UM) tumorigenesis. In some instances, about 80% of UM cases have been detected to contain a mutation in GNAQ and/or GNA11.
  • mutations or modifications of the Gq ⁇ genes have been associated with congenital diseases. In some instances, mutations of Gq ⁇ have been observed in congenital diseases such as Port-Wine Stain and/or Sturge-Weber Syndrome.
  • G 12/13 ⁇ modulates actin cytoskeletal remodeling in cells and regulates cell processes through guanine nucleotide exchange factors (GEFs). GEFs participate in the activation of small GTPases which acts as molecular switches in a variety of intracellular signaling pathways. Examples of small GTPases include the Ras-related GTPase superfamily (e.g., Rho family such as Cdc42), which is involved in cell differentiation, proliferation, cytoskeletal organization, vesicle trafficking, and nuclear transport.
  • GEFs guanine nucleotide exchange factors
  • the GPCRs that interact with G 12/13 ⁇ include, but are not limited to, purinergic receptors (e.g., P2Y1, P2Y2, P2Y4, P2Y6); muscarinic acetylcholine receptors M1 and M3; receptors for thrombin [protease-activated receptor (PAR)-l, PAR-2]; thromboxane (TXA2); sphingosine 1-phosphate (e.g., S1P 2 , S1P 3 , S1P 4 and S1P 5 ); lysophosphatidic acid (e.g., LPA 1 , LPA 2 , LPA 3 ); angiotensin II (AT1); serotonin (5-HT 2c and 5-HT 4 ); somatostatin (sst 5 ); endothelin (ETA and ETB); cholecystokinin (CCK1); V1a vasopressin receptors
  • purinergic receptors
  • G 12/13 ⁇ is further subdivided into G 12 and G 13 types which are encoded by GNA12 and GNA13, respectively.
  • Gi/o Family G i/o ⁇ (G inhibitory, G other) (also known as G i /G o or G i protein) suppresses the production of 3’, 5’-cyclic AMP (cAMP) from adenosine triphosphate (ATP) through an inhibition of adenylate cyclase activity, which converts ATP to cAMP.
  • G inhibitory, G other also known as G i /G o or G i protein
  • the GPCRs that interact with Gi ⁇ include, but are not limited to, 5-hydroxytryptamine receptor (5-HT receptor) types 5-HT 1 and 5-HT 5 ; muscarinic acetylcholine receptors such as M2 and M4; adenosine receptors such as A1 and A3; adrenergic receptors such as ⁇ 2A, ⁇ 2B, and ⁇ 2c; apelin receptors; calcium-sensing receptor; cannabinoid receptors CB1 and CB2; chemokine CXCR4 receptor; dopamines D 2 , D 3 , and D 4 ; GABA B receptor; glutamate receptors such as metabotropic glutamate receptor 2 (mGluR2), metabotropic glutamate receptor 3 (mGluR3), metabotropic glutamate receptor 4 (mGluR4), metabotropic glutamate receptor 6 (mGluR6), metabotropic glutamate receptor 7 (mGluR7), and metabotropic gluta
  • 5-HT receptor 5-hydroxy
  • Gi ⁇ 1, Gi ⁇ 2, Gi ⁇ 3, Gi ⁇ 4, Go ⁇ , Gt, Ggust, and G z there are several types of Gi ⁇ : Gi ⁇ 1, Gi ⁇ 2, Gi ⁇ 3, Gi ⁇ 4, Go ⁇ , Gt, Ggust, and G z .
  • G i ⁇ 1 is encoded by GNAI1.
  • G i ⁇ 2 is encoded by GNAI2.
  • G i ⁇ 3 is encoded by GNAI3.
  • G o ⁇ the ⁇ o subunit, is encoded by GNAO1.
  • Gt is encoded by GNAT1 and GNAT2.
  • Ggust is encoded by GNAT3.
  • Gz is encoded by GNAZ.
  • G s Family [00201] G s ⁇ (also known as G stimulatory, G s alpha subunit, or G s protein) activates the cAMP- dependent pathway through the activation of adenylate cyclase, which convers adenosine triphosphate (ATP) to 3’,5’-cyclic AMP (cAMP) and pyrophosphate.
  • G stimulatory, G s alpha subunit, or G s protein activates the cAMP- dependent pathway through the activation of adenylate cyclase, which convers adenosine triphosphate (ATP) to 3’,5’-cyclic AMP (cAMP) and pyrophosphate.
  • ATP adenosine triphosphate
  • cAMP cyclic AMP
  • the GPCRs that interact with G s ⁇ include, but are not limited to, 5-hydroxytryptamine receptor (5-HT receptor) types 5-HT4, 5-HT6, and 5-HT7; adrenocorticotropic hormone receptor (ACTH receptor) (also known as melanocortin receptor 2 or MC2R); adenosine receptor types A2a and A2b; arginine vasopressin receptor 2 (AVPR2); ⁇ -adrenergic receptors ⁇ 1 , ⁇ 2 , and ⁇ 3 ; calcitonin receptor; calcitonin gene-related peptide receptor; corticotropin-releasing hormone receptor; dopamine receptor D1-like family receptors such as D1 and D5; follicle-stimulating hormone receptor (FSH- receptor); gastric inhibitory polypeptide receptor; glucagon receptor; histamine H 2 receptor; luteinizing hormone/choriogonadotropin receptor; melanocortin receptors such as MC1
  • Gs there are two types of Gs ⁇ : Gs and Golf.
  • Gs is encoded by GNAS.
  • Golf is encoded by GNAL.
  • Additional Regulators of the Hippo signaling network is the Crumbs (Crb) complex.
  • the Crumbs complex is a key regulator of cell polarity and cell shape.
  • the Crumbs complex comprises transmembrane CRB proteins which assemble multi-protein complexes that function in cell polarity.
  • CRB complexes recruit members of the Angiomotin (AMOT) family of adaptor proteins that interact with the Hippo pathway components.
  • AMOT Angiomotin
  • the additional regulator of the Hippo signaling pathway comprises regulators of the MST kinase family. MST kinases monitor actin cytoskeletal integrity. In some instances, the regulators include TAO kinases and cell polarity kinase PAR-1. [00205] In some instances, the additional regulator of the Hippo signaling pathway comprises molecules of the adherens junction. In some instances, E-Cadherin (E-cad) suppresses YAP nuclear localization and activity through regulating MST activity.
  • E-cad E-Cadherin
  • E-cad- associated protein a-catenin regulates YAP through sequestering YAP/14-3-3 complexes in the cytoplasm.
  • Ajuba protein family members interact with Lats1/2 kinase activity, thereby preventing inactivation of YAP/TAZ.
  • additional proteins that interact with YAP/TAZ either directly or indirectly include, but are not limited to, Merlin, protocadherin Fat 1, MASK1/2, HIPK2, PTPN14, RASSF, PP2A, Salt-inducible kinases (SIKs), Scribble (SCRIB), the Scribble associated proteins Discs large (Dlg), KIBRA, PTPN14, NPHP3, LKB1, Ajuba, and ZO1/2.
  • the compounds described herein are inhibitors of transcriptional coactivator with PDZ binding motif/Yes-associated protein transcriptional coactivator (TAZ/YAP).
  • the compounds described herein increase the phosphorylation of transcriptional coactivator with PDZ binding motif/Yes-associated protein transcriptional coactivator (TAZ/YAP) or decrease the dephosphorylation of transcriptional coactivator with PDZ binding motif/Yes-associated protein transcriptional coactivator (TAZ/YAP). In some embodiments, the compounds increase the ubiquitination of transcriptional coactivator with PDZ binding motif/Yes-associated protein transcriptional coactivator (TAZ/YAP) or decrease the deubiquitination of transcriptional coactivator with PDZ binding motif/Yes-associated protein transcriptional coactivator (TAZ/YAP).
  • the compounds disclosed herein are inhibitors of one or more of the proteins encompassed by, or related to, the Hippo pathway.
  • an inhibitor of the Hippo pathway is an inhibitor of a G-protein and/or its coupled GPCR.
  • an inhibitor of the Hippo pathway is an inhibitor of a G-protein.
  • an inhibitor of the Hippo pathway is an inhibitor of the G q ⁇ family proteins such as G q , G q/11 , G q/14 , and G q/15 ; the G 12/13 ⁇ family of proteins such as G 12 and G 13 ; or the G i ⁇ family of proteins such as Gi ⁇ 1, Gi ⁇ 2, Gi ⁇ 3, Gi ⁇ 4, Go ⁇ , Gt, Ggust, and Gz.
  • an inhibitor of the Hippo pathway is an inhibitor of Gq.
  • an inhibitor of the Hippo pathway is an inhibitor of G q/11 .
  • an inhibitor of the Hippo pathway is an inhibitor of Gq/14.
  • an inhibitor of the Hippo pathway is an inhibitor of Gq/15.
  • an inhibitor of the Hippo pathway is an inhibitor of G12. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of G 13 . In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gi ⁇ 1. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gi ⁇ 2. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of G i ⁇ 3. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of G i ⁇ 4. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of G o ⁇ . In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gt. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Ggust.
  • an inhibitor of the Hippo pathway is an inhibitor of G z .
  • an inhibitor of the Hippo pathway is an inhibitor of a core protein of the Hippo pathway.
  • an inhibitor of the Hippo pathway is an inhibitor of Sav1.
  • an inhibitor of the Hippo pathway is an inhibitor of Mob.
  • an inhibitor of the Hippo pathway is an inhibitor of YAP.
  • an inhibitor of the Hippo pathway is an inhibitor of TAZ.
  • an inhibitor of the Hippo pathway is an inhibitor of TEAD.
  • an inhibitor of the Hippo pathway is an inhibitor of a protein associated with the ubiquitination and proteasomal degradation pathway.
  • an inhibitor of the Hippo pathway is an inhibitor of a proteasomal degradation pathway protein (e.g., 26S proteasome).
  • an inhibitor of the Hippo pathway is an inhibitor of a protein of the Ras superfamily of proteins.
  • an inhibitor of the Hippo pathway is an inhibitor of a protein of the Rho family of proteins.
  • an inhibitor of the Hippo pathway is an inhibitor of Cdc42.
  • Cdc42 is a member of the Ras superfamily of small GTPases. Specifically, Cdc42 belongs to the Rho family of GTPases, in which the family members participate in diverse and critical cellular processes such as gene transcription, cell-cell adhesion, and cell cycle progression.
  • an inhibitor of Cdc42 is involved in cell growth and polarity, and in some instances, Cdc42 is activated by guanine nucleotide exchange factors (GEFs). In some cases, an inhibitor of Cdc42 is a compound disclosed herein. [00213] In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a deubiquitinating enzyme. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a cysteine protease or a metalloprotease. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of an ubiquitin-specific protease. USP47 is a member of the ubiquitin-specific protease (USP/UBP) superfamily of cysteine proteases.
  • the compounds disclosed herein are inhibitors of USP47.
  • the present invention provides a use of a compound, or a pharmaceutical salt or composition thereof, for treating one or more disorders, diseases, and/or conditions wherein the disorder, disease, or condition includes, but is not limited to, a cellular proliferative disorder.
  • the activity of a compound utilized in this invention as an inhibitor of TEAD e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4
  • TEAD4 e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4
  • a variant or mutant thereof can be assayed in vitro, in vivo or in a cell line.
  • In vitro assays include assays that determine inhibition of TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4), or a variant or mutant thereof. Alternate in vitro assays quantitate the ability of the inhibitor to bind to TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) or a variant or mutant thereof.
  • TEAD1, TEAD2, TEAD3, and/or TEAD4 Detailed conditions for assaying a compound utilized in this invention as an inhibitor of TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4), or a variant or mutant thereof, are set forth in the Examples below. See, for example, Examples 2 and 5.
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein.
  • treatment can be administered after one or more symptoms have developed.
  • treatment can be administered in the absence of symptoms.
  • treatment can be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment can also be continued after symptoms have resolved, for example, to prevent or delay their recurrence.
  • the provided compounds are inhibitors of TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) and are therefore useful for treating one or more disorders associated with activity of TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4).
  • TEAD e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4
  • the present invention provides a method for treating a TEAD-mediated disorder comprising the step of administering to a patient in need thereof a therapeutically effective compound of the present invention, or pharmaceutically acceptable composition thereof.
  • TEAD-mediated disorders, diseases, and/or conditions means any disease or other deleterious condition in which TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4), or a variant or mutant thereof, is known to play a role. Accordingly, another aspect or embodiment of the present invention relates to treating or lessening the severity of one or more diseases in which TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4), or a variant or mutant thereof, are known to play a role.
  • TEAD e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4
  • a therapeutically effective amount of refers to the amount of a TEAD inhibitor or a pharmaceutically acceptable salt thereof, which is effective to reduce or attenuate the biological activity of TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) or a variant or mutant thereof, provide a therapeutic benefit in the treatment of a condition, or to delay or minimize one or more symptoms associated with the condition in a biological sample or in a patient.
  • TEAD e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4
  • a therapeutically effective amount of refers to the amount of a TEAD inhibitor or a pharmaceutically acceptable salt thereof that measurably decreases the binding or signaling activity of TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4), or a variant or mutant thereof or any TEAD-mediated activity.
  • the term “therapeutically effective amount” can encompass, in some embodiments, an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and/or enhances the therapeutic efficacy of another therapeutic agent.
  • a therapeutically effective amount is an amount sufficient for inhibition of a TEAD transcription factor.
  • a therapeutically effective amount is an amount sufficient for treating a proliferative disease.
  • TEAD1, TEAD2, TEAD3, and/or TEAD4 expression and/or increased TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) activity
  • TEAD e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4
  • TEAD1, TEAD2, TEAD3, and/or TEAD4 activity comprising the step of administering to a patient in need thereof a therapeutically effective compound of the present invention, or pharmaceutically acceptable composition thereof.
  • provided herein are methods of treating, reducing the severity of, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof of a disease or disorder in which inhibition or antagonizing of TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) activity is beneficial comprising the step of administering to a patient in need thereof a therapeutically effective compound of the present invention, or pharmaceutically acceptable composition thereof.
  • TEAD e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4
  • provided herein are methods of treating, reducing the severity of, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptms thereof of a disease or disorder in which inhibition or antagonizing of the Hippo pathway is beneficial comprising the step of administering to a patient in need thereof a therapeutically effective compound of the present invention, or pharmaceutically acceptable composition thereof.
  • the present invention provides a method for treating one or more disorders, diseases, and/or conditions wherein the disorder, disease, or condition includes, but is not limited to, a cellular proliferative disorder, comprising administering to a patient in need thereof, a TEAD inhibitor compound as described herein, or a pharmaceutical salt or composition thereof.
  • a cellular proliferative disorder is cancer.
  • the cancer is characterized by increased TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) expression and/or increased TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) activity.
  • an increase can be by at least about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 2-fold, about 3-fold, about 4- fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20- fold, about 25-fold, about 50-fold, about 100-fold, or higher, relative to a control or baseline amount of a function, or activity, or concentration.
  • the terms “increased expression” and/or “increased activity” of a substance, such as TEAD, in a sample or cancer or patient refers to an increase in the amount of the substance, such as TEAD, of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 25-fold, about 50- fold, about 100-fold, or higher, relative to the amount of the substance, such as TEAD, in a control sample or control samples, such as an individual or group of individuals who are not suffering from the disease or disorder (e.g.,
  • a subject can also be determined to have an “increased expression” or “increased activity” of TEAD if the expression and/or activity of TEAD is increased by one standard deviation, two standard deviations, three standard deviations, four standard deviations, five standard deviations, or more, relative to the mean (average) or median amount of TEAD in a control group of samples or a baseline group of samples or a retrospective analysis of patient samples.
  • control or baseline expression levels can be previously determined, or measured prior to the measurement in the sample or cancer or subject, or can be obtained from a database of such control samples.
  • a proliferative disease refers to a disease that occurs due to abnormal growth or extension by the multiplication of cells (Walker, Cambridge Dictionary of Biology, Cambridge University Press: Cambridge, UK, 1990).
  • a proliferative disease can be associated with: 1) the pathological proliferation of normally quiescent cells; 2) the pathological migration of cells from their normal location (e.g., metastasis of neoplastic cells); 3) the pathological expression of proteolytic enzymes, such as the matrix metalloproteinases (e.g., collagenases, gelatinases, and elastases); or 4) the pathological angiogenesis as in proliferative retinopathy and tumor metastasis.
  • proteolytic enzymes such as the matrix metalloproteinases (e.g., collagenases, gelatinases, and elastases)
  • the pathological angiogenesis as in proliferative retinopathy and tumor metastasis.
  • Exemplary proliferative diseases include cancers (i.e., “malignant neoplasms”), benign neoplasms, angiogenesis, inflammatory diseases, and autoimmune diseases.
  • Cancer i.e., “malignant neoplasms”
  • the cancer or proliferative disorder or tumor to be treated using the compounds and methods and uses described herein include, but are not limited to, a hematological cancer, a lymphoma, a myeloma, a leukemia, a neurological cancer, skin cancer, breast cancer, a prostate cancer, a colorectal cancer, lung cancer, head and neck cancer, a gastrointestinal cancer, a liver cancer, a pancreatic cancer, a genitourinary cancer, a bone cancer, renal cancer, and a vascular cancer.
  • a cancer is mediated by activation of transcriptional coactivator with PDZ binding motif/Yes-associated protein transcription coactivator (TAZ/YAP).
  • a cancer is mediated by modulation of the interaction of YAP/TAZ with TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4).
  • TEAD e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4
  • the cancer is characterized by or associated with increased TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) expression and/or increased TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) activity.
  • the cancer is a cancer in which YAP is localized in the nucleus of the cancer cells.
  • the cancer is characterized or associated with a genetic alteration in one or more Hippo pathway genes.
  • the term “genetic alteration in one or more Hippo pathway genes” refers to that certain percentage of cells in a sample, such as a tumor sample, having a detectable amount of genetic alteration in one or more Hippo pathway genes.
  • a genetic alteration in a gene can refer, for example, to a loss-of-function mutation in the gene (including, for example, frameshifts, nonsense mutations and splicing mutations), a change in gene copy number (including, for example, copy gain, amplification, copy loss, or deletion), or a fusion of the gene with another gene, such as, for example, a TAZ-CAMTA1 fusion or YAP1-TFE3 fusion.
  • genetic alteration in Hippo pathway genes refers to that about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, or 100% of cells, such as tumor cells, in a sample have at least about three copies of genetically altered Hippo pathway genes, at least about four copies of genetically altered Hippo pathway genes, at least about five copies of genetically altered Hippo pathway genes, at least about six copies of genetically altered Hippo pathway genes, at least about seven copies of genetically altered Hippo pathway genes, at least about eight copies of genetically altered Hippo pathway genes, at least about nine copies of genetically altered Hippo pathway genes, at least about ten copies of genetically altered Hippo pathway genes, at least about eleven copies of genetically altered Hippo pathway genes, at least about twelve copies of genetically altered Hippo pathway genes,
  • genetic alteration in Hippo pathway genes refers to that about 10% tumor cells in a sample have at least about 15 copies of genetically altered Hippo pathway genes. In some embodiments, genetic alteration in Hippo pathway genes refers to that about 40% tumor cells in a sample have at least about 4 copies of genetically altered Hippo pathway genes. In some embodiments, genetic alteration in Hippo pathway genes refers to that about 10% tumor cells in a sample have at least about four copies of genetically altered Hippo pathway genes. In some embodiments, a Hippo pathway gene is NF2. In some embodiments, the genetic alteration in the one or more Hippo pathway genes is NF2 deficiency. In some embodiments, NF2 deficiency refers to NF2 loss of function mutations.
  • NF2 deficiency refers to NF2 copy losses or deletions. In some embodiments, NF2 deficiency refers to absent or very low NF2 mRNA expression.
  • a Hippo pathway gene is YAP1. In some embodiments, the genetic alteration in the one or more Hippo pathway genes is YAP1 amplification. In some embodiments, the genetic alteration in the one or more Hippo pathway genes is a YAP1 fusion, such as a YAP1-TFE3 fusion. In some embodiments, a Hippo pathway gene is TAZ. In some embodiments, the genetic alteration in the one or more Hippo pathway genes is TAZ amplification.
  • the genetic alteration in the one or more Hippo pathway genes is a TAZ fusion, such as a TAZ-CAMTA1 fusion.
  • a Hippo pathway gene is LATS 1/2.
  • the genetic alteration in the one or more Hippo pathway genes is LATS 1/2 copy number loss or deletion.
  • a Hippo pathway gene is MST1/2.
  • a Hippo pathway gene is BAP1.
  • a cancer is characterized by a mutant G ⁇ -protein.
  • a mutant G ⁇ -protein is selected from G12, G13, Gq, G11, Gi, Go, and Gs.
  • a mutant G ⁇ -protein is G12.
  • a mutant G ⁇ -protein is G13. In some embodiments, a mutant G ⁇ -protein is Gq. In some embodiments, a mutant G ⁇ -protein is G11 . In some embodiments, a mutant G ⁇ -protein is Gi. In some embodiments, a mutant G ⁇ -protein is Go. In some embodiments, a mutant G ⁇ -protein is Gs. [00229] In some embodiments of the methods and uses described herein, a cancer is treated by inhibiting or reducing or decreasing or arresting further growth or spread of the cancer or tumor.
  • a cancer is treated by inhibiting or reducing the size (e.g., volume or mass) of the cancer or tumor by at least 5%, at least 10%, at least 25%, at least 50%, at least 75%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% relative to the size of the cancer or tumor prior to treatment.
  • size e.g., volume or mass
  • a cancer is treated by reducing the quantity of the cancers or tumors in the patient by at least 5%, at least 10%, at least 25%, at least 50%, at least 75%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% relative to the quantity of the cancers or tumors prior to treatment.
  • a patient treated using the methods or uses described herein exhibits progression-free survival of at least about one month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about one year, at least about eighteen months, at least about two years, at least about three years, at least about four years, or at least about five years after the treatment is initiated.
  • a patient treated using the methods or uses described herein exhibits an overall survival of at least about one month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about one year, at least about 14 months, at least about 16 months, at least about 18 months, at least about 20 months, at least about 22 months, at least about two years, at least about three years, at least about four years, or at least about five years after the treatment is initiated.
  • a patient treated using the methods or uses described herein exhibits an objective response rate (ORR) of at least about 15%, at least about 20%, at least about 25%, at least about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%.
  • ORR objective response rate
  • the cancer is lung cancer, thyroid cancer, ovarian cancer, colorectal cancer, prostate cancer, cancer of the pancreas, cancer of the esophagus, liver cancer, breast cancer, skin cancer, or mesothelioma.
  • the cancer is lung cancer, thyroid cancer, ovarian cancer, colorectal cancer, prostate cancer, cancer of the pancreas, cancer of the esophagus, liver cancer, breast cancer, skin cancer, or mesothelioma, sarcoma, or epithelioid hemangioendothelioma (EHE).
  • the cancer is mesothelioma, such as malignant mesothelioma.
  • the cancer is EHE.
  • cancer includes, without limitation, leukemias (e.g., acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (e.g., Hodgkin’s disease or non-Hodgkin’s disease), Waldenstrom's macroglobulinemia, multiple myeloma, heavy chain disease, and solid tumors such as sarcomas and carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcom
  • leukemias e
  • the cancer is glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, or retinoblastoma.
  • GBM glioblastoma multiforme
  • medulloblastoma craniopharyngioma
  • ependymoma pinealoma
  • hemangioblastoma acoustic neuroma
  • oligodendroglioma schwannoma
  • neurofibrosarcoma meningioma, melanoma
  • neuroblastoma
  • the cancer is acoustic neuroma, astrocytoma (e.g., Grade I – Pilocytic Astrocytoma, Grade II – Low-grade Astrocytoma, Grade III – Anaplastic Astrocytoma, or Grade IV – Glioblastoma (GBM)), chordoma, CNS lymphoma, craniopharyngioma, brain stem glioma, ependymoma, mixed glioma, optic nerve glioma, subependymoma, medulloblastoma, meningioma, metastatic brain tumor, oligodendroglioma, pituitary tumors, primitive neuroectodermal (PNET) tumor, or schwannoma.
  • astrocytoma e.g., Grade I – Pilocytic Astrocytoma, Grade II – Low-grade Astrocytoma, Grade III – Anaplastic Astrocytoma, or Grade IV
  • the cancer is a type found more commonly in children than adults, such as brain stem glioma, craniopharyngioma, ependymoma, juvenile pilocytic astrocytoma (JPA), medulloblastoma, optic nerve glioma, pineal tumor, primitive neuroectodermal tumors (PNET), or rhabdoid tumor.
  • the patient is an adult human. In some embodiments, the patient is a child or pediatric patient.
  • Cancer includes, in another embodiment, without limitation, mesothelioma, hepatobilliary (hepatic and billiary duct), bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal (gastric, colorectal, and duodenal), uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin’s Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia,
  • the cancer is selected from hepatocellular carcinoma, ovarian cancer, ovarian epithelial cancer, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatocholangiocarcinoma; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing sarcoma; anaplastic thyroid cancer; adrenocortical adenoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma; gastrointestinal/stomach (GIST) cancer; lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; glioma, or brain cancer; neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MP
  • the cancer is selected from hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial cancer, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenocortical adenoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom’s macroglobulinemia, or medulloblastoma.
  • HCC hepatocellular carcinoma
  • hepatoblastoma colon cancer
  • rectal cancer ovarian cancer
  • a cancer is a solid tumor, such as a sarcoma, carcinoma, or lymphoma.
  • Solid tumors generally comprise an abnormal mass of tissue that typically does not include cysts or liquid areas.
  • the cancer is selected from renal cell carcinoma, or kidney cancer; hepatocellular carcinoma (HCC) or hepatoblastoma, or liver cancer; melanoma; breast cancer; colorectal carcinoma, or colorectal cancer; colon cancer; rectal cancer; anal cancer; lung cancer, such as non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC); ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatocholangiocarcinoma; soft tissue and bone synovial sarcoma; rhabdomy
  • the cancer is selected from renal cell carcinoma, hepatocellular carcinoma (HCC), hepatoblastoma, colorectal carcinoma, colorectal cancer, colon cancer, rectal cancer, anal cancer, ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, brain cancer, neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom’s macroglobulinemia, or medulloblastoma.
  • HCC hepato
  • the cancer is selected from hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom’s macroglobulinemia, or medulloblastoma.
  • HCC hepatocellular carcinoma
  • hepatoblastoma colon cancer
  • rectal cancer ovarian cancer
  • ovarian cancer ova
  • the cancer is hepatocellular carcinoma (HCC). In some embodiments, the cancer is hepatoblastoma. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is rectal cancer. In some embodiments, the cancer is ovarian cancer, or ovarian carcinoma. In some embodiments, the cancer is ovarian epithelial cancer. In some embodiments, the cancer is fallopian tube cancer. In some embodiments, the cancer is papillary serous cystadenocarcinoma. In some embodiments, the cancer is uterine papillary serous carcinoma (UPSC). In some embodiments, the cancer is hepatocholangiocarcinoma.
  • HCC hepatocellular carcinoma
  • the cancer is hepatoblastoma. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is rectal cancer. In some embodiments, the cancer is ovarian cancer, or ovarian carcinoma. In some embodiments, the cancer is ovarian epithelial cancer. In some embodiments,
  • the cancer is soft tissue and bone synovial sarcoma. In some embodiments, the cancer is rhabdomyosarcoma. In some embodiments, the cancer is osteosarcoma. In some embodiments, the cancer is anaplastic thyroid cancer. In some embodiments, the cancer is adrenocortical carcinoma. In some embodiments, the cancer is pancreatic cancer, or pancreatic ductal carcinoma. In some embodiments, the cancer is pancreatic adenocarcinoma. In some embodiments, the cancer is glioma. In some embodiments, the cancer is malignant peripheral nerve sheath tumors (MPNST). In some embodiments, the cancer is neurofibromatosis-1 associated MPNST.
  • MPNST peripheral nerve sheath tumors
  • a cancer is Waldenstrom’s macroglobulinemia. In some embodiments, the cancer is medulloblastoma.
  • a cancer is a viral-associated cancer, including human immunodeficiency virus (HIV) associated solid tumors, human papilloma virus (HPV)-16 positive incurable solid tumors, and adult T-cell leukemia, which is caused by human T-cell leukemia virus type I (HTLV-I) and is a highly aggressive form of CD4+ T-cell leukemia characterized by clonal integration of HTLV-I in leukemic cells (See https://clinicaltrials.gov/ct2/show/study/ NCT02631746); as well as virus-associated tumors in gastric cancer, nasopharyngeal carcinoma, cervical cancer, vaginal cancer, vulvar cancer, squamous cell carcinoma of the head and neck, and Merkel cell carcinoma.
  • HCV human immunodeficiency virus
  • HPV human papilloma virus
  • a cancer is melanoma cancer.
  • a cancer is breast cancer.
  • a cancer is lung cancer.
  • a cancer is small cell lung cancer (SCLC).
  • SCLC small cell lung cancer
  • NSCLC non-small cell lung cancer
  • the compounds and compositions, according to the methods of the present invention can be administered using any amount and any route of administration effective for treating or lessening the severity of a cancer or tumor.
  • the exact amount required varies from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease or condition, the particular agent, its mode of administration, and the like.
  • Compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.
  • dosage unit form refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention is decided by the attending physician within the scope of sound medical judgment.
  • the specific effective dose level for any particular patient or organism depends upon a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts.
  • patient or “subject”, as used herein, means an animal, preferably a mammal, and most preferably a human.
  • compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the disease or disorder being treated.
  • the compounds of the invention can be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents,
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • a compound of the present invention In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide- polyglycolide.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl
  • the dosage form may also comprise buffering agents.
  • Solid compositions of a similar type can also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They can optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • embedding compositions examples include polymeric substances and waxes. Solid compositions of a similar type can also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like. [00254]
  • the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention.
  • the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body.
  • Such dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin.
  • the rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • Co-Administration with One or More Other Therapeutic Agent(s) [00256] Depending upon the particular condition, or disease, to be treated, additional therapeutic agents that are normally administered to treat that condition, can also be present in the compositions of this invention.
  • the present invention provides a method of treating a disclosed disease or condition comprising administering to a patient in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof and co-administering simultaneously or sequentially an effective amount of one or more additional therapeutic agents, such as those described herein.
  • the method includes co-administering one additional therapeutic agent.
  • the method includes co-administering two additional therapeutic agents.
  • the combination of the disclosed compound and the additional therapeutic agent or agents acts synergistically.
  • a compound of the current invention can also be used in combination with known therapeutic processes, for example, the administration of hormones or radiation.
  • a provided compound is used as a radiosensitizer, especially for the treatment of tumors which exhibit poor sensitivity to radiotherapy.
  • a compound of the current invention can be administered alone or in combination with one or more other therapeutic compounds, possible combination therapy taking the form of fixed combinations or the administration of a compound of the invention and one or more other therapeutic compounds being staggered or given independently of one another, or the combined administration of fixed combinations and one or more other therapeutic compounds.
  • a compound of the current invention can besides, or in addition, be administered especially for tumor therapy in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination of these.
  • One or more other therapeutic agent(s) may be administered separately from a compound or composition of the invention, as part of a multiple dosage regimen. Alternatively, one or more other therapeutic agent(s) may be part of a single dosage form, mixed together with a compound of this invention in a single composition.
  • one or more other therapeutic agent(s) and a compound or composition of the invention can be administered simultaneously, sequentially or within a period of time from one another, for example within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 18, 20, 21, 22, 23, or 24 hours from one another.
  • one or more other therapeutic agent(s) and a compound or composition of the invention are administered as a multiple dosage regimen within greater than 24 hours apart.
  • the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this invention.
  • a compound of the present invention can be administered with one or more other therapeutic agent(s) simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form.
  • the present invention provides a single unit dosage form comprising a compound of the current invention, one or more other therapeutic agent(s), and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • a pharmaceutically acceptable carrier, adjuvant, or vehicle e.g., a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • a composition of the invention should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of a compound of the invention can be administered.
  • the one or more other therapeutic agent(s) and a compound of the invention may act synergistically. Therefore, the amount of the one or more other therapeutic agent(s) in such compositions may be less than that required in a monotherapy utilizing only that therapeutic agent.
  • a dosage of between 0.01 – 1,000 ⁇ g/kg body weight/day of the one or more other therapeutic agent(s) can be administered.
  • the amount of one or more other therapeutic agent present in the compositions of this invention may be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent.
  • the amount of one or more other therapeutic agent(s) in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.
  • one or more other therapeutic agent(s) is administered at a dosage of about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% of the amount normally administered for that agent.
  • the phrase “normally administered” means the amount an FDA approved therapeutic agent is approved for dosing per the FDA label insert.
  • the compounds of this invention, or pharmaceutical compositions thereof may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters.
  • vascular stents for example, have been used to overcome restenosis (re-narrowing of the vessel wall after injury).
  • patients using stents or other implantable devices risk clot formation or platelet activation. These unwanted effects may be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor.
  • Implantable devices coated with a compound of this invention are another embodiment of the present invention.
  • one or more other therapeutic agent is a Poly ADP ribose polymerase (PARP) inhibitor.
  • PARP Poly ADP ribose polymerase
  • a PARP inhibitor is selected from olaparib (LYNPARZA®, AstraZeneca); rucaparib (RUBRACA®, Clovis Oncology); niraparib (ZEJULA®, Tesaro); talazoparib (MDV3800/BMN 673/LT00673, Medivation/Pfizer/Biomarin); veliparib (ABT-888, AbbVie); and BGB-290 (BeiGene, Inc.).
  • one or more other therapeutic agent is a histone deacetylase (HDAC) inhibitor.
  • HDAC histone deacetylase
  • an HDAC inhibitor is selected from vorinostat (ZOLINZA®, Merck); romidepsin (ISTODAX®, Celgene); panobinostat (FARYDAK®, Novartis); belinostat (BELEODAQ®, Spectrum Pharmaceuticals); entinostat (SNDX-275, Syndax Pharmaceuticals) (NCT00866333); and chidamide (EPIDAZA®, HBI-8000, Chipscreen Biosciences, China).
  • one or more other therapeutic agent is a CDK inhibitor, such as a CDK4/CDK6 inhibitor.
  • a CDK 4/6 inhibitor is selected from palbociclib (IBRANCE®, Pfizer); ribociclib (KISQALI®, Novartis); abemaciclib (Ly2835219, Eli Lilly); and trilaciclib (G1T28, G1 Therapeutics).
  • one or more other therapeutic agent is a phosphatidylinositol 3 kinase (PI3K) inhibitor.
  • a PI3K inhibitor is selected from idelalisib (ZYDELIG®, Gilead), alpelisib (BYL719, Novartis), taselisib (GDC-0032, Genentech/Roche); pictilisib (GDC-0941, Genentech/Roche); copanlisib (BAY806946, Bayer); duvelisib (formerly IPI-145, Infinity Pharmaceuticals); PQR309 (Piqur Therapeutics, Switzerland); and TGR1202 (formerly RP5230, TG Therapeutics).
  • one or more other therapeutic agent is a platinum-based therapeutic, also referred to as platins.
  • a platinum-based therapeutic is selected from cisplatin (PLATINOL®, Bristol-Myers Squibb); carboplatin (PARAPLATIN®, Bristol-Myers Squibb; also, Teva; Pfizer); oxaliplatin (ELOXITIN® Sanofi-Aventis); nedaplatin (AQUPLA®, Shionogi), picoplatin (Poniard Pharmaceuticals); and satraplatin (JM-216, Agennix).
  • one or more other therapeutic agent is a taxane compound, which causes disruption of microtubules, which are essential for cell division.
  • a taxane compound is selected from paclitaxel (TAXOL®, Bristol-Myers Squibb), docetaxel (TAXOTERE®, Sanofi-Aventis; DOCEFREZ®, Sun Pharmaceutical), albumin-bound paclitaxel (ABRAXANE®; Abraxis/Celgene), cabazitaxel (JEVTANA®, Sanofi-Aventis), and SID530 (SK Chemicals, Co.) (NCT00931008).
  • one or more other therapeutic agent is a nucleoside inhibitor, or a therapeutic agent that interferes with normal DNA synthesis, protein synthesis, cell replication, or will otherwise inhibit rapidly proliferating cells.
  • a nucleoside inhibitor is selected from trabectedin (guanidine alkylating agent, YONDELIS®, Janssen Oncology), mechlorethamine (alkylating agent, VALCHLOR®, Aktelion Pharmaceuticals); vincristine (ONCOVIN®, Eli Lilly; VINCASAR®, Teva Pharmaceuticals; MARQIBO®, Talon Therapeutics); temozolomide (prodrug to alkylating agent 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC) TEMODAR®, Merck); cytarabine injection (ara-C, antimetabolic cytidine analog, Pfizer); lomustine (alkylating
  • one or more other therapeutic agent is a kinase inhibitor or VEGF-R antagonist.
  • one or more other therapeutic agent is a MEK inhibitor.
  • a “MEK inhibitor” refers to any inhibitor or blocker or antagonist that binds to and/or inhibits mitogen-activated protein kinase enzymes MEK1 and/or MEK2.
  • an MEK inhibitor is selected from those as described in Cheng et al., “Current Development Status of MEK Inhibitors,” Molecules 2017, 22, 1551, the contents of which are incorporated herein by reference in its entirety.
  • the MEK inhibitor is selected from binimetinib (MEK162, ARRY-438162, ARRAY BIOPHARMA INC.), cobimetinib(COTELLIC®, Exelexis/Genentech/Roche), refametinib (BAY 86–9766, RDEA119; Bayer AG), selumetinib (AZD6244, ARRY-142886; ASTRAZENECA), trametinib(MEKINIST®, Novartis), mirdametinib(PD-0325901, Spring Works Therapeutics), pimasertib (AS703026, MSC1936369B, Merck KGaA)or a pharmaceutically acceptable salt and/or solvate of any of the foregoing.
  • binimetinib MEK162, ARRY-438162, ARRAY BIOPHARMA INC.
  • cobimetinib(COTELLIC® Exelexis/Genentech/Roche
  • the second anti-cancer agent is binimetinib, cobimetinib, selumetinib, trametinib, mirdametinib, pimasertib, or a pharmaceutically acceptable salt and/or solvate of any of the foregoing.
  • MEK inhibitors for use as an other therapeutic agent in the methods and uses described herein include, but are not limited to, E6201 (Eisai Co Ltd./Strategia Theraputics), GDC-0623 (RG 7421, Genentech, Inc.), CH5126766 (RO5126766, Chugai 232Pharmaceutical Co., Roche), HL-085 (Shanghai Kechow Pharma, Inc.), SHR7390 (HENGRUI MEDICINE), TQ-B3234 (CHIATAI TIANQING), CS-3006 (CSTONE Pharmaceuticals), FCN-159 (FosunPharmaceuticals), VS-6766 (Verastem Oncology), and IMM-1-104 (Immuneering Corp.).
  • MEK inhibitors for use as second anti- cancer agents in the methods and uses described herein include, but are not limited to, those described in WO2005/121142, WO2014/169843, WO2016/035008, WO2016/168704, WO2020/125747, WO2021/142144, WO2021/142345, WO2021/149776, the contents of each of which are herein incorporated by reference in their entireties.
  • one or more other therapeutic agent is an EGFR inhibitor.
  • an “EGFR inhibitor” refers to any inhibitor or blocker or antagonist that binds to and/or inhibits epidermal growth factor receptor (EGFR).
  • an EGFR inhibitor is selected from those as described in Ayati et al., “A review on progression of epidermal growth factor receptor (EGFR) inhibitors as an efficient approach in cancer targeted therapy,” Bioorganic Chemistry 2020, 99: 103811, the contents of which are incorporated herein by reference in its entirety.
  • an EGFR inhibitor is selected from cetuximab, necitumumab, panitumumab, zalutumumab, nimotuzumab, and matuzumab.
  • an EGFR inhibitor is cetuximab.
  • an EGFR inhibitor is necitumumab.
  • an EGFR inhibitor is panitumumab. In some embodiments, an EGFR inhibitor is zalutumumab. In some embodiments, an EGFR inhibitor is nimotuzumab. In some embodiments, an EGFR inhibitor is matuzumab. [0001] In some embodiments, an EGFR inhibitor is selected from osimertinib, gefitinib, erlotinib, lapatinib, neratinib, vandetanib, afatinib, brigatinib, dacomitinib, and icotinib. In some embodiments, an EGFR inhibitor is Osimertinib.
  • an EGFR inhibitor is gefitinib. In some embodiments, an EGFR inhibitor is erlotinib. In some embodiments, an EGFR inhibitor is lapatinib. In some embodiments, an EGFR inhibitor is neratinib. In some embodiments, an EGFR inhibitor is vandetanib. In some embodiments, an EGFR inhibitor is afatinib. In some embodiments, an EGFR inhibitor is brigatinib. In some embodiments, an EGFR inhibitor is dacomitinib. In some embodiments, an EGFR inhibitor is icotinib.
  • an EGFR inhibitor is a “1st generation EGFR tyrosine kinase inhibitor” (1st generation TKI).
  • a 1 st generation TKI refers to reversible EGFR inhibitors, such as gefitinib and erlotinib, which are effective in first-line treatment of NSCLC harboring EGFR activating mutations such as deletions in exon 19 and exon 21 L858R mutation.
  • an EGFR inhibitor is a “2nd generation EGFR tyrosine kinase inhibitor” (2nd generation TKI).
  • a 2 nd generation TKI refers to covalent irreversible EGFR inhibitors, such as afatinib and dacomitib, which are effective in first-line treatment of NSCLC harboring EGFR activating mutations such as deletions in exon 19 and exon 21 L858R mutation.
  • an EGFR inhibitor is a “3rd generation EGFR tyrosine kinase inhibitor” (3rd generation TKI).
  • a 3rd generation TKI refers to covalent irreversible EGFR inhibitors, such as osimertinib and lazertinib, which are selective to the EGFR activating mutations, such as deletions in exon 19 and exon 21 L858R, alone or in combination with T790M mutation, and have lower inhibitory activity against wild-type EGFR.
  • one or more other therapeutic agent is selected from approved VEGF inhibitors and kinase inhibitors useful in the present invention include: bevacizumab (AVASTIN®, Genentech/Roche) an anti-VEGF monoclonal antibody; ramucirumab (CYRAMZA®, Eli Lilly), an anti-VEGFR-2 antibody and ziv-aflibercept, also known as VEGF Trap (ZALTRAP®; Regeneron/Sanofi).
  • bevacizumab AVASTIN®, Genentech/Roche
  • ramucirumab CYRAMZA®, Eli Lilly
  • ZALTRAP® ziv-aflibercept
  • VEGFR inhibitors such as regorafenib (STIVARGA®, Bayer); vandetanib (CAPRELSA®, AstraZeneca); axitinib (INLYTA®, Pfizer); and lenvatinib (LENVIMA®, Eisai); Raf inhibitors, such as sorafenib (NEXAVAR®, Bayer AG and Onyx); dabrafenib (TAFINLAR®, Novartis); and vemurafenib (ZELBORAF®, Genentech/Roche); MEK inhibitors, such as cobimetanib (COTELLIC®, Exelexis/Genentech/Roche); trametinib (MEKINIST®, Novartis); Bcr-Abl tyrosine kinase inhibitors, such as imatinib (GLEEVEC®, Novartis); nilotinib (TASIGNA®, Novartis); dasatinib (
  • kinase inhibitors and VEGF-R antagonists that are in development and may be used in the present invention include tivozanib (Aveo Pharmaecuticals); vatalanib (Bayer/Novartis); lucitanib (Clovis Oncology); dovitinib (TKI258, Novartis); Chiauanib (Chipscreen Biosciences); CEP-11981 (Cephalon); linifanib (Abbott Laboratories); neratinib (HKI-272, Puma Biotechnology); radotinib (SUPECT®, IY5511, Il-Yang Pharmaceuticals, S.
  • one or more other therapeutic agent is an mTOR inhibitor, which inhibits cell proliferation, angiogenesis and glucose uptake.
  • an mTOR inhibitor is everolimus (AFINITOR®, Novartis); temsirolimus (TORISEL®, Pfizer); and sirolimus (RAPAMUNE®, Pfizer).
  • one or more other therapeutic agent is a proteasome inhibitor.
  • Approved proteasome inhibitors useful in the present invention include bortezomib (VELCADE®, Takeda); carfilzomib (KYPROLIS®, Amgen); and ixazomib (NINLARO®, Takeda).
  • one or more other therapeutic agent is a growth factor antagonist, such as an antagonist of platelet-derived growth factor (PDGF), or epidermal growth factor (EGF) or its receptor (EGFR).
  • Approved PDGF antagonists which may be used in the present invention include olaratumab (LARTRUVO®; Eli Lilly).
  • Approved EGFR antagonists which may be used in the present invention include cetuximab (ERBITUX®, Eli Lilly); necitumumab (PORTRAZZA®, Eli Lilly), panitumumab (VECTIBIX®, Amgen); and osimertinib (targeting activated EGFR, TAGRISSO®, AstraZeneca).
  • one or more other therapeutic agent is an aromatase inhibitor.
  • an aromatase inhibitor is selected from exemestane (AROMASIN®, Pfizer); anastazole (ARIMIDEX®, AstraZeneca) and letrozole (FEMARA®, Novartis).
  • one or more other therapeutic agent is an antagonist of the hedgehog pathway.
  • Approved hedgehog pathway inhibitors which may be used in the present invention include sonidegib (ODOMZO®, Sun Pharmaceuticals); and vismodegib (ERIVEDGE®, Genentech), both for treatment of basal cell carcinoma.
  • one or more other therapeutic agent is a folic acid inhibitor. Approved folic acid inhibitors useful in the present invention include pemetrexed (ALIMTA®, Eli Lilly).
  • one or more other therapeutic agent is a CC chemokine receptor 4 (CCR4) inhibitor.
  • CCR4 inhibitors being studied that may be useful in the present invention include mogamulizumab (POTELIGEO®, Kyowa Hakko Kirin, Japan).
  • one or more other therapeutic agent is an isocitrate dehydrogenase (IDH) inhibitor.
  • IDH inhibitors being studied which may be used in the present invention include AG120 (Celgene; NCT02677922); AG221 (Celgene, NCT02677922; NCT02577406); BAY1436032 (Bayer, NCT02746081); IDH305 (Novartis, NCT02987010).
  • one or more other therapeutic agent is an arginase inhibitor.
  • Arginase inhibitors being studied which may be used in the present invention include AEB1102 (pegylated recombinant arginase, Aeglea Biotherapeutics), which is being studied in Phase 1 clinical trials for acute myeloid leukemia and myelodysplastic syndrome (NCT02732184) and solid tumors (NCT02561234); and CB-1158 (Calithera Biosciences).
  • one or more other therapeutic agent is a glutaminase inhibitor.
  • Glutaminase inhibitors being studied which may be used in the present invention include CB-839 (Calithera Biosciences).
  • one or more other therapeutic agent is an antibody that binds to tumor antigens, that is, proteins expressed on the cell surface of tumor cells.
  • Approved antibodies that bind to tumor antigens which may be used in the present invention include rituximab (RITUXAN®, Genentech/BiogenIdec); ofatumumab (anti-CD20, ARZERRA®, GlaxoSmithKline); obinutuzumab (anti-CD20, GAZYVA®, Genentech), ibritumomab (anti- CD20 and Yttrium-90, ZEVALIN®, Spectrum Pharmaceuticals); daratumumab (anti-CD38, DARZALEX®, Janssen Biotech), dinutuximab (anti-glycolipid GD2, UNITUXIN®, United Therapeutics); trastuzumab (anti-HER2, HERCEPTIN®, Genentech); ado-trastuzumab em
  • one or more other therapeutic agent is a topoisomerase inhibitor.
  • Approved topoisomerase inhibitors useful in the present invention include irinotecan (ONIVYDE®, Merrimack Pharmaceuticals); topotecan (HYCAMTIN®, GlaxoSmithKline).
  • Topoisomerase inhibitors being studied which may be used in the present invention include pixantrone (PIXUVRI®, CTI Biopharma).
  • one or more other therapeutic agent is an inhibitor of anti- apoptotic proteins, such as BCL-2.
  • Approved anti-apoptotics which may be used in the present invention include venetoclax (VENCLEXTA®, AbbVie/Genentech); and blinatumomab (BLINCYTO®, Amgen).
  • Other therapeutic agents targeting apoptotic proteins which have undergone clinical testing and may be used in the present invention include navitoclax (ABT-263, Abbott), a BCL-2 inhibitor (NCT02079740).
  • one or more other therapeutic agent is an androgen receptor inhibitor.
  • Approved androgen receptor inhibitors useful in the present invention include enzalutamide (XTANDI®, Astellas/Medivation); approved inhibitors of androgen synthesis include abiraterone (ZYTIGA®, Centocor/Ortho); approved antagonist of gonadotropin-releasing hormone (GnRH) receptor (degaralix, FIRMAGON®, Ferring Pharmaceuticals).
  • one or more other therapeutic agent is a selective estrogen receptor modulator (SERM), which interferes with the synthesis or activity of estrogens.
  • SERMs useful in the present invention include raloxifene (EVISTA®, Eli Lilly).
  • one or more other therapeutic agent is an inhibitor of bone resorption.
  • An approved therapeutic which inhibits bone resorption is Denosumab (XGEVA®, Amgen), an antibody that binds to RANKL, prevents binding to its receptor RANK, found on the surface of osteoclasts, their precursors, and osteoclast-like giant cells, which mediates bone pathology in solid tumors with osseous metastases.
  • Other approved therapeutics that inhibit bone resorption include bisphosphonates, such as zoledronic acid (ZOMETA®, Novartis).
  • one or more other therapeutic agent is an inhibitor of interaction between the two primary p53 suppressor proteins, MDMX and MDM2.
  • Inhibitors of p53 suppression proteins being studied which may be used in the present invention include ALRN- 6924 (Aileron), a stapled peptide that equipotently binds to and disrupts the interaction of MDMX and MDM2 with p53.
  • ALRN-6924 is currently being evaluated in clinical trials for the treatment of AML, advanced myelodysplastic syndrome (MDS) and peripheral T-cell lymphoma (PTCL) (NCT02909972; NCT02264613).
  • one or more other therapeutic agent is an inhibitor of transforming growth factor-beta (TGF-beta or TGF- ⁇ ).
  • Inhibitors of TGF-beta proteins being studied which may be used in the present invention include NIS793 (Novartis), an anti-TGF-beta antibody being tested in the clinic for treatment of various cancers, including breast, lung, hepatocellular, colorectal, pancreatic, prostate and renal cancer (NCT 02947165).
  • the inhibitor of TGF-beta proteins is fresolimumab (GC1008; Sanofi-Genzyme), which is being studied for melanoma (NCT00923169); renal cell carcinoma (NCT00356460); and non-small cell lung cancer (NCT02581787).
  • the additional therapeutic agent is a TGF-beta trap, such as described in Connolly et al. (2012) Int’l J. Biological Sciences 8:964-978.
  • TGF-beta trap such as described in Connolly et al. (2012) Int’l J. Biological Sciences 8:964-978.
  • M7824 Merck KgaA - formerly MSB0011459X
  • NCT02699515 a bispecific, anti-PD- L1/TGF- ⁇ trap compound
  • NCT02517398 NCT02517398
  • M7824 is comprised of a fully human IgG1 antibody against PD-L1 fused to the extracellular domain of human TGF-beta receptor II, which functions as a TGF- ⁇ “trap.”
  • one or more other therapeutic agent is selected from glembatumumab vedotin-monomethyl auristatin E (MMAE) (Celldex), an anti-glycoprotein NMB (gpNMB) antibody (CR011) linked to the cytotoxic MMAE.
  • gpNMB is a protein overexpressed by multiple tumor types associated with cancer cells’ ability to metastasize.
  • one or more other therapeutic agents is an antiproliferative compound.
  • antiproliferative compounds include, but are not limited to aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active compounds; alkylating compounds; histone deacetylase inhibitors; compounds which induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antineoplastic antimetabolites; platin compounds; compounds targeting/decreasing a protein or lipid kinase activity and further anti-angiogenic compounds; compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase; gonadorelin agonists; anti-androgens; methionine aminopeptidase inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds used in
  • aromatase inhibitor as used herein relates to a compound which inhibits estrogen production, for instance, the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively.
  • the term includes, but is not limited to steroids, especially atamestane, exemestane and formestane and, in particular, non-steroids, especially aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole and letrozole.
  • Exemestane is marketed under the trade name AROMASINTM.
  • Formestane is marketed under the trade name LENTARONTM. Fadrozole is marketed under the trade name AFEMATM. Anastrozole is marketed under the trade name ARIMIDEXTM. Letrozole is marketed under the trade names FEMARATM or FEMArTM. Aminoglutethimide is marketed under the trade name ORIMETENTM.
  • a combination of the invention comprising a chemotherapeutic agent which is an aromatase inhibitor is particularly useful for the treatment of hormone receptor positive tumors, such as breast tumors.
  • the term "antiestrogen” as used herein relates to a compound which antagonizes the effect of estrogens at the estrogen receptor level.
  • Tamoxifen is marketed under the trade name NOLVADEXTM.
  • Raloxifene hydrochloride is marketed under the trade name EVISTATM.
  • Fulvestrant can be administered under the trade name FASLODEXTMFulvestrant can be administered under the trade name FaslodexTM.
  • a combination of the invention comprising a chemotherapeutic agent which is an antiestrogen is particularly useful for the treatment of estrogen receptor positive tumors, such as breast tumors.
  • anti-androgen as used herein relates to any substance which is capable of inhibiting the biological effects of androgenic hormones and includes, but is not limited to, bicalutamide (CASODEXTM).
  • CASODEXTM bicalutamide
  • gonadorelin agonist as used herein includes, but is not limited to abarelix, goserelin, and goserelin acetate. Goserelin can be administered under the trade name ZOLADEXTM.
  • topoisomerase I inhibitor includes, but is not limited to topotecan, gimatecan, irinotecan, camptothecian and its analogues, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148.
  • Irinotecan can be administered, e.g., in the form as it is marketed, e.g., under the trademark CAMPTOSARTM.
  • Topotecan is marketed under the trade name HYCAMPTINTM.
  • topoisomerase II inhibitor includes, but is not limited to the anthracyclines such as doxorubicin (including liposomal formulation, such as CAELYXTM), daunorubicin, epirubicin, idarubicin and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophillotoxines etoposide and teniposide.
  • Etoposide is marketed under the trade name ETOPOPHOSTM.
  • Teniposide is marketed under the trade name VM 26-Bristol
  • Doxorubicin is marketed under the trade name ACRIBLASTINTM or ADRIAMYCINTM.
  • microtubule active agent relates to microtubule stabilizing, microtubule destabilizing compounds and microtublin polymerization inhibitors including, but not limited to taxanes, such as paclitaxel and docetaxel; vinca alkaloids, such as vinblastine or vinblastine sulfate, vincristine or vincristine sulfate, and vinorelbine; discodermolides; cochicine and epothilones and derivatives thereof.
  • Paclitaxel is marketed under the trade name TAXOLTM.
  • Docetaxel is marketed under the trade name TAXOTERETM.
  • Vinblastine sulfate is marketed under the trade name VINBLASTIN R.PTM.
  • Vincristine sulfate is marketed under the trade name FARMISTINTM.
  • alkylating agent includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU or Gliadel).
  • Cyclophosphamide is marketed under the trade name CYCLOSTINTM. Ifosfamide is marketed under the trade name HOLOXANTM.
  • histone deacetylase inhibitors or "HDAC inhibitors” relates to compounds which inhibit the histone deacetylase and which possess antiproliferative activity. This includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).
  • antiproliferative activity This includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).
  • antiproliferative activity This includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).
  • antiproliferative activity includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).
  • antiproliferative activity includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).
  • antiproliferative activity includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).
  • antiproliferative activity includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).
  • Gemcitabine is marketed under the trade name GEMZARTM.
  • the term "platin compound" as used herein includes, but is not limited to, carboplatin, cis-platin, cisplatinum and oxaliplatin.
  • Carboplatin can be administered, e.g., in the form as it is marketed, e.g., under the trademark CARBOPLATTM.
  • Oxaliplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark ELOXATINTM.
  • the term "compounds targeting/decreasing a protein or lipid kinase activity; or a protein or lipid phosphatase activity; or further anti-angiogenic compounds” as used herein includes, but is not limited to, protein tyrosine kinase and/or serine and/or threonine kinase inhibitors or lipid kinase inhibitors, such as a) compounds targeting, decreasing or inhibiting the activity of the platelet-derived growth factor-receptors (PDGFR), such as compounds which target, decrease or inhibit the activity of PDGFR, especially compounds which inhibit the PDGF receptor, such as an N-phenyl-2-pyrimidine-amine derivative, such as imatinib, SU101, SU6668 and GFB- 111; b) compounds targeting, decreasing or inhibiting the activity of the fibroblast growth factor- receptors (FGFR); c) compounds targeting, decreasing or inhibiting the activity of the insulin-like growth factor receptor I (IGF
  • PI3K inhibitor includes, but is not limited to compounds having inhibitory activity against one or more enzymes in the phosphatidylinositol-3-kinase family, including, but not limited to PI3K ⁇ , PI3K ⁇ , PI3K ⁇ , PI3K ⁇ , PI3K-C2 ⁇ , PI3K-C2 ⁇ , PI3K-C2 ⁇ , PI3K- C2 ⁇ , Vps34, p110- ⁇ , p110- ⁇ , p110- ⁇ , p110- ⁇ , p85- ⁇ , p85- ⁇ , p55- ⁇ , p150, p101, and p87.
  • PI3K inhibitors useful in this invention include but are not limited to ATU-027, SF-1126, DS- 7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib.
  • Bcl-2 inhibitor includes, but is not limited to compounds having inhibitory activity against B-cell lymphoma 2 protein (Bcl-2), including but not limited to ABT-199, ABT-731, ABT-737, apogossypol, Ascenta’s pan-Bcl-2 inhibitors, curcumin (and analogs thereof), dual Bcl-2/Bcl-xL inhibitors (Infinity Pharmaceuticals/Novartis Pharmaceuticals), Genasense (G3139), HA14-1 (and analogs thereof; see WO2008118802), navitoclax (and analogs thereof, see US7390799), NH-1 (Shenayng Pharmaceutical University), obatoclax (and analogs thereof, see WO2004106328), S-001 (Gloria Pharmaceuticals), TW series compounds (Univ.
  • Bcl-2 inhibitor as used herein includes, but is not limited to compounds having inhibitory activity against Bruton’s Tyrosine Kinase (BTK), including, but not limited to AVL-292 and ibrutinib.
  • SYK inhibitor includes, but is not limited to compounds having inhibitory activity against spleen tyrosine kinase (SYK), including but not limited to PRT- 062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib.
  • SYK spleen tyrosine kinase
  • Further examples of BTK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in WO2008039218 and WO2011090760, the entirety of which are incorporated herein by reference.
  • SYK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in WO2003063794, WO2005007623, and WO2006078846, the entirety of which are incorporated herein by reference.
  • PI3K inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in WO2004019973, WO2004089925, WO2007016176, US8138347, WO2002088112, WO2007084786, WO2007129161, WO2006122806, WO2005113554, and WO2007044729 the entirety of which are incorporated herein by reference.
  • JAK inhibitory compounds and conditions treatable by such compounds in combination with compounds of this invention can be found in WO2009114512, WO2008109943, WO2007053452, WO2000142246, and WO2007070514, the entirety of which are incorporated herein by reference.
  • Further anti-angiogenic compounds include compounds having another mechanism for their activity, e.g., unrelated to protein or lipid kinase inhibition e.g., thalidomide (THALOMIDTM) and TNP-470.
  • TAALOMIDTM thalidomide
  • proteasome inhibitors useful for use in combination with compounds of the invention include, but are not limited to bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP-18770, and MLN9708.
  • Compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase are e.g., inhibitors of phosphatase 1, phosphatase 2A, or CDC25, such as okadaic acid or a derivative thereof.
  • Compounds which induce cell differentiation processes include, but are not limited to, retinoic acid, ⁇ - ⁇ - or ⁇ - tocopherol or ⁇ - ⁇ - or ⁇ -tocotrienol.
  • the term cyclooxygenase inhibitor as used herein includes, but is not limited to, Cox- 2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives, such as celecoxib ( [00324] CELEBREXTM), rofecoxib (VIOXXTM), etoricoxib, valdecoxib or a 5-alkyl-2- arylaminophenylacetic acid, such as 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenyl acetic acid, lumiracoxib.
  • bisphosphonates includes, but is not limited to, etridonic, clodronic, tiludronic, pamidronic, alendronic, ibandronic, risedronic and zoledronic acid.
  • Etridonic acid is marketed under the trade name DIDRONELTM.
  • Clodronic acid is marketed under the trade name BONEFOSTM.
  • Tiludronic acid is marketed under the trade name SkelidTM.
  • Pamidronic acid is marketed under the trade name AREDIATM.
  • Alendronic acid is marketed under the trade name FOSAMAXTM.
  • Ibandronic acid is marketed under the trade name BONDRANATTM.
  • Risedronic acid is marketed under the trade name ACTONELTM.
  • Zoledronic acid is marketed under the trade name ZOMETATM.
  • mTOR inhibitors relates to compounds which inhibit the mammalian target of rapamycin (mTOR) and which possess antiproliferative activity such as sirolimus (RAPAMUNE®), everolimus (CERTICANTM), CCI-779 and ABT578.
  • heparanase inhibitor refers to compounds which target, decrease or inhibit heparin sulfate degradation. The term includes, but is not limited to, PI-88.
  • biological response modifier refers to a lymphokine or interferons.
  • inhibitor of Ras oncogenic isoforms such as H-Ras, K-Ras, or N-Ras
  • telomerase inhibitor refers to compounds which target, decrease or inhibit the activity of telomerase.
  • Compounds which target, decrease or inhibit the activity of telomerase are especially compounds which inhibit the telomerase receptor, such as telomestatin.
  • methionine aminopeptidase inhibitor refers to compounds which target, decrease or inhibit the activity of methionine aminopeptidase.
  • compounds which target, decrease or inhibit the activity of methionine aminopeptidase include, but are not limited to, bengamide or a derivative thereof.
  • proteasome inhibitor refers to compounds which target, decrease or inhibit the activity of the proteasome.
  • Compounds which target, decrease or inhibit the activity of the proteasome include, but are not limited to, Bortezomib (VELCADETM) and MLN 341.
  • matrix metalloproteinase inhibitor or (“MMP” inhibitor) as used herein includes, but is not limited to, collagen peptidomimetic and nonpeptidomimetic inhibitors, tetracycline derivatives, e.g., hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogue marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551) BMS-279251, BAY 12-9566, TAA211 , MMI270B or AAJ996.
  • MMP matrix metalloproteinase inhibitor
  • FMS-like tyrosine kinase inhibitors which are compounds targeting, decreasing or inhibiting the activity of FMS-like tyrosine kinase receptors (Flt-3R); interferon, 1- ⁇ -D-arabinofuransylcytosine (ara-c) and bisulfan; and ALK inhibitors, which are compounds which target, decrease or inhibit anaplastic lymphoma kinase.
  • FMS-like tyrosine kinase receptors are especially compounds, proteins or antibodies which inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, a staurosporine derivative, SU11248 and MLN518.
  • HSP90 inhibitors includes, but is not limited to, compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90; degrading, targeting, decreasing or inhibiting the HSP90 client proteins via the ubiquitin proteosome pathway.
  • Compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90 are especially compounds, proteins or antibodies which inhibit the ATPase activity of HSP90, such as 17-allylamino,17-demethoxygeldanamycin (17AAG), a geldanamycin derivative; other geldanamycin related compounds; radicicol and HDAC inhibitors.
  • antiproliferative antibodies includes, but is not limited to, trastuzumab (HERCEPTINTM), Trastuzumab-DM1, erbitux, bevacizumab (AVASTINTM), rituximab (RITUXAN ® ), PRO64553 (anti-CD40) and 2C4 Antibody.
  • antibodies is meant intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least 2 intact antibodies, and antibodies fragments so long as they exhibit the desired biological activity.
  • compounds of the current invention can be used in combination with standard leukemia therapies, especially in combination with therapies used for the treatment of AML.
  • compounds of the current invention can be administered in combination with, for example, farnesyl transferase inhibitors and/or other drugs useful for the treatment of AML, such as Daunorubicin, Adriamycin, Ara-C, VP-16, Teniposide, Mitoxantrone, Idarubicin, Carboplatinum and PKC412.
  • HDAC histone deacetylase
  • SAHA suberoylanilide hydroxamic acid
  • HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228), Trichostatin A and compounds disclosed in US 6,552,065 including, but not limited to, N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]- amino]methyl]phenyl]- 2E-2-propenamide, or a pharmaceutically acceptable salt thereof and N-hydroxy-3-[4-[(2- hydroxyethyl) ⁇ 2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2- propenamide, or a pharmaceutically acceptable salt thereof, especially the lactate salt.
  • Somatostatin receptor antagonists as used herein refer to compounds which target, treat or inhibit the somatostatin receptor such as octreotide, and SOM230.
  • Tumor cell damaging approaches refer to approaches such as ionizing radiation.
  • ionizing radiation means ionizing radiation that occurs as either electromagnetic rays (such as X-rays and gamma rays) or particles (such as alpha and beta particles). Ionizing radiation is provided in, but not limited to, radiation therapy and is known in the art.
  • EDG binders and ribonucleotide reductase inhibitors.
  • EDG binders refers to a class of immunosuppressants that modulates lymphocyte recirculation, such as FTY720.
  • ribonucleotide reductase inhibitors refers to pyrimidine or purine nucleoside analogs including, but not limited to, fludarabine and/or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C against ALL) and/or pentostatin.
  • Ribonucleotide reductase inhibitors are especially hydroxyurea or 2-hydroxy-1H-isoindole-1 ,3-dione derivatives.
  • VEGF vascular endothelial growth factor
  • compounds, proteins or monoclonal antibodies of VEGF such as 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate; ANGIOSTATINTM; ENDOSTATINTM; anthranilic acid amides; ZD4190; Zd6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies, such as rhuMAb and RHUFab, VEGF aptamer such as Macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibody, Angiozyme (RPI 4610) and Bevacizumab (AVASTINTM).
  • VEGF aptamer such as Macugon
  • Photodynamic therapy refers to therapy which uses certain chemicals known as photosensitizing compounds to treat or prevent cancers. Examples of photodynamic therapy include treatment with compounds, such as VISUDYNETM and porfimer sodium.
  • Angiostatic steroids as used herein refers to compounds which block or inhibit angiogenesis, such as, e.g., anecortave, triamcinolone, hydrocortisone, 11- ⁇ -epihydrocotisol, cortexolone, 17 ⁇ -hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone and dexamethasone.
  • Implants containing corticosteroids refers to compounds, such as fluocinolone and dexamethasone.
  • Other chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormonal compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or miscellaneous compounds or compounds with other or unknown mechanism of action.
  • the structure of the active compounds identified by code numbers, generic or trade names may be taken from the actual edition of the standard compendium "The Merck Index" or from databases, e.g., Patents International (e.g., IMS World Publications).
  • one or more other therapeutic agent is an immuno-oncology agent.
  • an immuno-oncology agent refers to an agent which is effective to enhance, stimulate, and/or up-regulate immune responses in a subject.
  • the administration of an immuno-oncology agent with a compound of the invention has a synergic effect in treating a cancer.
  • An immuno-oncology agent can be, for example, a small molecule drug, an antibody, or a biologic or small molecule.
  • biologic immuno-oncology agents include, but are not limited to, cancer vaccines, antibodies, and cytokines.
  • an antibody is a monoclonal antibody. In some embodiments, a monoclonal antibody is humanized or human.
  • an immuno-oncology agent is (i) an agonist of a stimulatory (including a co-stimulatory) receptor or (ii) an antagonist of an inhibitory (including a co- inhibitory) signal on T cells, both of which result in amplifying antigen-specific T cell responses.
  • Certain of the stimulatory and inhibitory molecules are members of the immunoglobulin super family (IgSF).
  • B7 family includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6.
  • B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6 includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6.
  • TNF family of molecules that bind to cognate TNF receptor family members which includes CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL/Apo2-L, TRAILR1/DR4, TRAILR2/DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR/Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LT ⁇ R, LIGHT, DcR3, HVEM, VEGI/TL1A, TRAMP/DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1, Lymphotoxin ⁇ /TNF ⁇ , TNFR2, TNF ⁇ , LT ⁇ R, Lymphotoxin ⁇ 1 ⁇ 2, FA
  • an immuno-oncology agent is a cytokine that inhibits T cell activation (e.g., IL-6, IL-10, TGF- ⁇ , VEGF, and other immunosuppressive cytokines) or a cytokine that stimulates T cell activation, for stimulating an immune response.
  • a combination of a compound of the invention and an immuno- oncology agent can stimulate T cell responses.
  • an immuno-oncology agent is: (i) an antagonist of a protein that inhibits T cell activation (e.g., immune checkpoint inhibitors) such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin 9, CEACAM-1, BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM- 4; or (ii) an agonist of a protein that stimulates T cell activation such as B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3 and CD28H.
  • T cell activation e.g., immune checkpoint inhibitors
  • an antagonist of a protein that inhibits T cell activation e.g.,
  • an immuno-oncology agent is an antagonist of inhibitory receptors on NK cells or an agonist of activating receptors on NK cells.
  • an immuno-oncology agent is an antagonist of KIR, such as lirilumab.
  • an immuno-oncology agent is an agent that inhibits or depletes macrophages or monocytes, including but not limited to CSF-1R antagonists such as CSF-1R antagonist antibodies including RG7155 (WO11/70024, WO11/107553, WO11/131407, WO13/87699, WO13/119716, WO13/132044) or FPA-008 (WO11/140249; WO13169264; WO14/036357).
  • CSF-1R antagonists such as CSF-1R antagonist antibodies including RG7155 (WO11/70024, WO11/107553, WO11/131407, WO13/87699, WO13/119716, WO13/132044) or FPA-008 (WO11/140249; WO13169264; WO14/036357).
  • an immuno-oncology agent is selected from agonistic agents that ligate positive costimulatory receptors, blocking agents that attenuate signaling through inhibitory receptors, antagonists, and one or more agents that increase systemically the frequency of anti-tumor T cells, agents that overcome distinct immune suppressive pathways within the tumor microenvironment (e.g., block inhibitory receptor engagement (e.g., PD-L1/PD-1 interactions), deplete or inhibit Tregs (e.g., using an anti-CD25 monoclonal antibody (e.g., daclizumab) or by ex vivo anti-CD25 bead depletion), inhibit metabolic enzymes such as IDO, or reverse/prevent T cell energy or exhaustion) and agents that trigger innate immune activation and/or inflammation at tumor sites.
  • block inhibitory receptor engagement e.g., PD-L1/PD-1 interactions
  • Tregs e.g., using an anti-CD25 monoclonal antibody (e.g., daclizumab) or by ex
  • an immuno-oncology agent is a CTLA-4 antagonist.
  • a CTLA-4 antagonist is an antagonistic CTLA-4 antibody.
  • an antagonistic CTLA-4 antibody is YERVOY (ipilimumab) or tremelimumab.
  • an immuno-oncology agent is a PD-1 antagonist.
  • a PD-1 antagonist is administered by infusion.
  • an immuno- oncology agent is an antibody or an antigen-binding portion thereof that binds specifically to a Programmed Death-1 (PD-1) receptor and inhibits PD-1 activity.
  • a PD-1 antagonist is an antagonistic PD-1 antibody.
  • an antagonistic PD-1 antibody is OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), or MEDI-0680 (AMP-514; WO2012/145493).
  • an immuno-oncology agent may be pidilizumab (CT- 011).
  • an immuno-oncology agent is a recombinant protein composed of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1, called AMP-224. [00355]
  • an immuno-oncology agent is a PD-L1 antagonist.
  • a PD-L1 antagonist is an antagonistic PD-L1 antibody.
  • a PD-L1 antibody is MPDL3280A (RG7446; WO2010/077634), durvalumab (MEDI4736), BMS- 936559 (WO2007/005874), and MSB0010718C (WO2013/79174).
  • an immuno-oncology agent is a LAG-3 antagonist.
  • a LAG-3 antagonist is an antagonistic LAG-3 antibody.
  • a LAG3 antibody is BMS-986016 (WO10/19570, WO14/08218), or IMP-731 or IMP-321 (WO08/132601, WO009/44273).
  • an immuno-oncology agent is a CD137 (4-1BB) agonist.
  • a CD137 (4-1BB) agonist is an agonistic CD137 antibody.
  • a CD137 antibody is urelumab or PF-05082566 (WO12/32433).
  • an immuno-oncology agent is a GITR agonist.
  • a GITR agonist is an agonistic GITR antibody.
  • a GITR antibody is BMS-986153, BMS-986156, TRX-518 (WO006/105021, WO009/009116), or MK- 4166 (WO11/028683).
  • an immuno-oncology agent is an indoleamine (2,3)- dioxygenase (IDO) antagonist.
  • an IDO antagonist is selected from epacadostat (INCB024360, Incyte); indoximod (NLG-8189, NewLink Genetics Corporation); capmanitib (INC280, Novartis); GDC-0919 (Genentech/Roche); PF-06840003 (Pfizer); BMS:F001287 (Bristol-Myers Squibb); Phy906/KD108 (Phytoceutica); an enzyme that breaks down kynurenine (Kynase, Ikena Oncology, formerly known as Kyn Therapeutics); and NLG-919 (WO09/73620, WO009/1156652, WO11/56652, WO12/142237).
  • an immuno-oncology agent is an OX40 agonist.
  • an OX40 agonist is an agonistic OX40 antibody.
  • an OX40 antibody is MEDI-6383 or MEDI-6469.
  • an immuno-oncology agent is an OX40L antagonist.
  • an OX40L antagonist is an antagonistic OX40 antibody.
  • an OX40L antagonist is RG-7888 (WO06/029879).
  • an immuno-oncology agent is a CD40 agonist.
  • a CD40 agonist is an agonistic CD40 antibody.
  • an immuno- oncology agent is a CD40 antagonist. In some embodiments, a CD40 antagonist is an antagonistic CD40 antibody. In some embodiments, a CD40 antibody is lucatumumab or dacetuzumab. [00363] In some embodiments, an immuno-oncology agent is a CD27 agonist. In some embodiments, a CD27 agonist is an agonistic CD27 antibody. In some embodiments, a CD27 antibody is varlilumab. [00364] In some embodiments, an immuno-oncology agent is MGA271 (to B7H3) (WO11/109400).
  • an immuno-oncology agent is abagovomab, adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab, atezolimab, avelumab, blinatumomab, BMS-936559, catumaxomab, durvalumab, epacadostat, epratuzumab, indoximod, inotuzumab ozogamicin, intelumumab, ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab, obinutuzumab, ocaratuzumab, ofatumumab, olatatumab, pembrolizumab, pidilizumab, rituximab,
  • an immuno-oncology agent is an immunostimulatory agent.
  • antibodies blocking the PD-1 and PD-L1 inhibitory axis can unleash activated tumor- reactive T cells and have been shown in clinical trials to induce durable anti-tumor responses in increasing numbers of tumor histologies, including some tumor types that conventionally have not been considered immunotherapy sensitive. See, e.g., Okazaki, T. et al. (2013) Nat. Immunol.14, 1212–1218; Zou et al. (2016) Sci. Transl. Med.8.
  • the anti-PD-1 antibody nivolumab (OPDIVO ® , Bristol-Myers Squibb, also known as ONO-4538, MDX1106 and BMS-936558), has shown potential to improve the overall survival in patients with RCC who had experienced disease progression during or after prior anti-angiogenic therapy.
  • the immunomodulatory therapeutic specifically induces apoptosis of tumor cells.
  • Approved immunomodulatory therapeutics which may be used in the present invention include pomalidomide (POMALYST®, Celgene); lenalidomide (REVLIMID®, Celgene); ingenol mebutate (PICATO®, LEO Pharma).
  • an immuno-oncology agent is a cancer vaccine.
  • the cancer vaccine is selected from sipuleucel-T (PROVENGE®, Dendreon/Valeant Pharmaceuticals), which has been approved for treatment of asymptomatic, or minimally symptomatic metastatic castrate-resistant (hormone-refractory) prostate cancer; and talimogene laherparepvec (IMLYGIC®, BioVex/Amgen, previously known as T-VEC), a genetically modified oncolytic viral therapy approved for treatment of unresectable cutaneous, subcutaneous and nodal lesions in melanoma.
  • sipuleucel-T PROVENGE®, Dendreon/Valeant Pharmaceuticals
  • IMLYGIC® BioVex/Amgen, previously known as T-VEC
  • an immuno-oncology agent is selected from an oncolytic viral therapy such as pexastimogene devacirepvec (PexaVec/JX-594, SillaJen/formerly Jennerex Biotherapeutics), a thymidine kinase- (TK-) deficient vaccinia virus engineered to express GM-CSF, for hepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312); pelareorep (REOLYSIN®, Oncolytics Biotech), a variant of respiratory enteric orphan virus (reovirus) which does not replicate in cells that are not RAS-activated, in numerous cancers, including colorectal cancer (NCT01622543); prostate cancer (NCT01619813); head and neck squamous cell cancer (NCT01166542); pancreatic adenocarcinoma (NCT00998322); and non-small cell lung cancer (NSCLC) (
  • an immuno-oncology agent is selected from JX-929 (SillaJen/formerly Jennerex Biotherapeutics), a TK- and vaccinia growth factor-deficient vaccinia virus engineered to express cytosine deaminase, which is able to convert the prodrug 5- fluorocytosine to the cytotoxic drug 5-fluorouracil; TG01 and TG02 (Targovax/formerly Oncos), peptide-based immunotherapy agents targeted for difficult-to-treat RAS mutations; and TILT-123 (TILT Biotherapeutics), an engineered adenovirus designated: Ad5/3-E2F-delta24-hTNF ⁇ -IRES- hIL20; and VSV-GP (ViraTherapeutics) a vesicular stomatitis virus (VSV) engineered to express the glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV), which can
  • an immuno-oncology agent is a T-cell engineered to express a chimeric antigen receptor, or CAR.
  • the T-cells engineered to express such chimeric antigen receptor are referred to as a CAR-T cells.
  • CARs have been constructed that consist of binding domains, which may be derived from natural ligands, single chain variable fragments (scFv) derived from monoclonal antibodies specific for cell-surface antigens, fused to endodomains that are the functional end of the T-cell receptor (TCR), such as the CD3-zeta signaling domain from TCRs, which is capable of generating an activation signal in T lymphocytes.
  • binding domains which may be derived from natural ligands, single chain variable fragments (scFv) derived from monoclonal antibodies specific for cell-surface antigens, fused to endodomains that are the functional end of the T-cell receptor (TCR), such as the CD3-zeta signaling domain from TCRs
  • the CAR-T cell is one of those described in U.S. Patent 8,906,682 (June et al.; hereby incorporated by reference in its entirety), which discloses CAR-T cells engineered to comprise an extracellular domain having an antigen binding domain (such as a domain that binds to CD19), fused to an intracellular signaling domain of the T cell antigen receptor complex zeta chain (such as CD3 zeta).
  • an antigen binding domain such as a domain that binds to CD19
  • CD3 zeta intracellular signaling domain of the T cell antigen receptor complex
  • an immunostimulatory agent is an activator of retinoic acid receptor-related orphan receptor o (ROR ot).
  • ROR ot is a transcription factor with key roles in the differentiation and maintenance of Type 17 effector subsets of CD4+ (Th17) and CD8+ (Tc17) T cells, as well as the differentiation of IL-17 expressing innate immune cell subpopulations such as NK cells.
  • an activator of ROR ot is LYC-55716 (Lycera), which is currently being evaluated in clinical trials for the treatment of solid tumors (NCT02929862).
  • an immunostimulatory agent is an agonist or activator of a toll- like receptor (TLR).
  • TLR toll- like receptor
  • Suitable activators of TLRs include an agonist or activator of TLR9 such as SD-101 (Dynavax).
  • SD-101 is an immunostimulatory CpG which is being studied for B-cell, follicular and other lymphomas (NCT02254772).
  • Agonists or activators of TLR8 which may be used in the present invention include motolimod (VTX-2337, VentiRx Pharmaceuticals) which is being studied for squamous cell cancer of the head and neck (NCT02124850) and ovarian cancer (NCT02431559).
  • immuno-oncology agents that can be used in the present invention include urelumab (BMS-663513, Bristol-Myers Squibb), an anti-CD137 monoclonal antibody; varlilumab (CDX-1127, Celldex Therapeutics), an anti-CD27 monoclonal antibody; BMS-986178 (Bristol- Myers Squibb), an anti-OX40 monoclonal antibody; lirilumab (IPH2102/BMS-986015, Innate Pharma, Bristol-Myers Squibb), an anti-KIR monoclonal antibody; monalizumab (IPH2201, Innate Pharma, AstraZeneca) an anti-NKG2A monoclonal antibody; andecaliximab (GS-5745, Gilead Sciences), an anti-MMP9 antibody; MK-4166 (Merck & Co.), an anti-GITR monoclonal antibody.
  • urelumab BMS-663513, Bristol-
  • an immunostimulatory agent is selected from elotuzumab, mifamurtide, an agonist or activator of a toll-like receptor, and an activator of ROR ot.
  • an immunostimulatory therapeutic is recombinant human interleukin 15 (rhIL-15). rhIL-15 has been tested in the clinic as a therapy for melanoma and renal cell carcinoma (NCT01021059 and NCT01369888) and leukemias (NCT02689453).
  • an immunostimulatory agent is recombinant human interleukin 12 (rhIL-12).
  • an IL-15 based immunotherapeutic is heterodimeric IL-15 (hetIL-15, Novartis/Admune), a fusion complex composed of a synthetic form of endogenous IL-15 complexed to the soluble IL-15 binding protein IL-15 receptor alpha chain (IL15:sIL-15RA), which has been tested in Phase 1 clinical trials for melanoma, renal cell carcinoma, non-small cell lung cancer and head and neck squamous cell carcinoma (NCT02452268).
  • a recombinant human interleukin 12 (rhIL-12) is NM-IL-12 (Neumedicines, Inc.), NCT02544724, or NCT02542124.
  • an immuno-oncology agent is selected from those descripted in Jerry L. Adams et al., “Big opportunities for small molecules in immuno-oncology,” Cancer Therapy 2015, Vol.14, pages 603-622, the content of which is incorporated herein by reference in its entirety.
  • an immuno-oncology agent is selected from the examples described in Table 1 of Jerry L. Adams et al.
  • an immuno-oncology agent is a small molecule targeting an immuno-oncology target selected from those listed in Table 2 of Jerry L. Adams et al.
  • an immuno-oncology agent is a small molecule agent selected from those listed in Table 2 of Jerry L. Adams et al.
  • an immuno-oncology agent is selected from the small molecule immuno-oncology agents described in Peter L. Toogood, “Small molecule immuno-oncology therapeutic agents,” Bioorganic & Medicinal Chemistry Letters 2018, Vol.28, pages 319-329, the content of which is incorporated herein by reference in its entirety.
  • an immuno-oncology agent is an agent targeting the pathways as described in Peter L. Toogood.
  • an immuno-oncology agent is selected from those described in Sandra L.
  • an immuno-oncology agent is a bispecific T cell engager (BITE®) antibody construct.
  • a bispecific T cell engager (BITE®) antibody construct is a CD19/CD3 bispecific antibody construct.
  • a bispecific T cell engager (BITE®) antibody construct is an EGFR/CD3 bispecific antibody construct.
  • a bispecific T cell engager (BITE®) antibody construct activates T cells.
  • a bispecific T cell engager (BITE®) antibody construct activates T cells, which release cytokines inducing upregulation of intercellular adhesion molecule 1 (ICAM-1) and FAS on bystander cells.
  • a bispecific T cell engager (BITE®) antibody construct activates T cells which result in induced bystander cell lysis.
  • the bystander cells are in solid tumors.
  • the bystander cells being lysed are in proximity to the BITE®-activated T cells.
  • the bystander cells comprises tumor-associated antigen (TAA) negative cancer cells.
  • the bystander cells comprise EGFR-negative cancer cells.
  • an immuno- oncology agent is an antibody which blocks the PD-L1/PD1 axis and/or CTLA4.
  • an immuno-oncology agent is an ex vivo expanded tumor-infiltrating T cell.
  • an immuno-oncology agent is a bispecific antibody construct or chimeric antigen receptors (CARs) that directly connect T cells with tumor-associated surface antigens (TAAs).
  • CARs chimeric antigen receptors
  • TAAs tumor-associated surface antigens
  • Exemplary Immune Checkpoint Inhibitors [00381]
  • an immuno-oncology agent is an immune checkpoint inhibitor as described herein. [00382]
  • the term “checkpoint inhibitor” as used herein relates to agents useful in preventing cancer cells from avoiding the immune system of the patient.
  • T-cell exhaustion results from chronic exposure to antigens that has led to up-regulation of inhibitory receptors.
  • inhibitory receptors serve as immune checkpoints in order to prevent uncontrolled immune reactions.
  • PD-1 and co-inhibitory receptors such as cytotoxic T-lymphocyte antigen 4 (CTLA-4, B and T Lymphocyte Attenuator (BTLA; CD272), T cell Immunoglobulin and Mucin domain-3 (Tim-3), Lymphocyte Activation Gene-3 (Lag-3; CD223), and others are often referred to as a checkpoint regulators.
  • an immune checkpoint inhibitor is an antibody to PD-1.
  • PD-1 binds to the programmed cell death 1 receptor (PD-1) to prevent the receptor from binding to the inhibitory ligand PDL-1, thus overriding the ability of tumors to suppress the host anti-tumor immune response.
  • the checkpoint inhibitor is a biologic therapeutic or a small molecule.
  • the checkpoint inhibitor is a monoclonal antibody, a humanized antibody, a fully human antibody, a fusion protein or a combination thereof.
  • the checkpoint inhibitor inhibits a checkpoint protein selected from CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands or a combination thereof.
  • a checkpoint protein selected from CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands or a combination thereof.
  • the checkpoint inhibitor interacts with a ligand of a checkpoint protein selected from CTLA-4, PDL1, PDL2, PDl, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands or a combination thereof.
  • the checkpoint inhibitor is an immunostimulatory agent, a T cell growth factor, an interleukin, an antibody, a vaccine or a combination thereof.
  • the interleukin is IL-7 or IL-15.
  • the interleukin is glycosylated IL-7.
  • the vaccine is a dendritic cell (DC) vaccine.
  • DC dendritic cell
  • Checkpoint inhibitors include any agent that blocks or inhibits in a statistically significant manner, the inhibitory pathways of the immune system. Such inhibitors may include small molecule inhibitors or may include antibodies, or antigen binding fragments thereof, that bind to and block or inhibit immune checkpoint receptors or antibodies that bind to and block or inhibit immune checkpoint receptor ligands.
  • Illustrative checkpoint molecules that can be targeted for blocking or inhibition include, but are not limited to, CTLA-4, PDL1, PDL2, PD1, B7-H3, B7- H4, BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, KIR, 2B4 (belongs to the CD2 family of molecules and is expressed on all NK, ⁇ , and memory CD8 + ( ⁇ ) T cells), CD160 (also referred to as BY55), CGEN-15049, CHK 1 and CHK2 kinases, A2aR, and various B-7 family ligands.
  • CTLA-4 CTLA-4, PDL1, PDL2, PD1, B7-H3, B7- H4, BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, KIR, 2B4 (belongs to the CD2 family of molecules and is expressed on all NK, ⁇ , and memory CD8 + ( ⁇ ) T cells
  • CD160 also referred to as BY55
  • B7 family ligands include, but are not limited to, B7- 1, B7-2, B7-DC, B7-H1, B7-H2, B7-H3, B7- H4, B7-H5, B7-H6 and B7-H7.
  • Checkpoint inhibitors include antibodies, or antigen binding fragments thereof, other binding proteins, biologic therapeutics, or small molecules, that bind to and block or inhibit the activity of one or more of CTLA-4, PDL1, PDL2, PD1, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD 160 and CGEN-15049.
  • Illustrative immune checkpoint inhibitors include, but are not limited to, Tremelimumab (CTLA-4 blocking antibody), anti-OX40, PD-L1 monoclonal Antibody (Anti-B7-Hl; MEDI4736), MK-3475 (PD-1 blocker), Nivolumab (anti-PD1 antibody), CT-011 (anti-PD1 antibody), BY55 monoclonal antibody, AMP224 (anti-PDL1 antibody), BMS- 936559 (anti-PDL1 antibody), MPLDL3280A (anti-PDL1 antibody), MSB0010718C (anti-PDL1 antibody), and ipilimumab (anti-CTLA-4 checkpoint inhibitor).
  • CTLA-4 blocking antibody PD-L1 monoclonal Antibody
  • Anti-B7-Hl MEDI4736
  • MK-3475 PD-1 blocker
  • Nivolumab anti-PD1 antibody
  • CT-011 anti-PD1 antibody
  • BY55 monoclonal antibody AMP
  • Checkpoint protein ligands include, but are not limited to PD-L1, PD-L2, B7-H3, B7- H4, CD28, CD86 and TIM-3.
  • the immune checkpoint inhibitor is selected from a PD-1 antagonist, a PD-L1 antagonist, and a CTLA-4 antagonist.
  • the checkpoint inhibitor is selected from the group consisting of nivolumab ( [00388] OPDIVO®), ipilimumab (YERVOY®), and pembrolizumab (KEYTRUDA®).
  • the checkpoint inhibitor is selected from nivolumab (anti-PD-1 antibody, OPDIVO®, Bristol-Myers Squibb); pembrolizumab (anti-PD-1 antibody, KEYTRUDA®, Merck); ipilimumab (anti-CTLA-4 antibody, YERVOY®, Bristol-Myers Squibb); durvalumab (anti-PD-L1 antibody, IMFINZI®, AstraZeneca); and atezolizumab (anti-PD-L1 antibody, TECENTRIQ®, Genentech).
  • nivolumab anti-PD-1 antibody, OPDIVO®, Bristol-Myers Squibb
  • pembrolizumab anti-PD-1 antibody, KEYTRUDA®, Merck
  • ipilimumab anti-CTLA-4 antibody, YERVOY®, Bristol-Myers Squibb
  • durvalumab anti-PD-L1 antibody, IMFINZI®,
  • the checkpoint inhibitor is selected from the group consisting of lambrolizumab (MK-3475), nivolumab (BMS-936558), pidilizumab (CT-011), AMP-224, MDX-1105, MEDI4736, MPDL3280A, BMS-936559, ipilimumab, lirlumab, IPH2101, pembrolizumab (KEYTRUDA®), and tremelimumab.
  • MK-3475 lambrolizumab
  • BMS-936558 nivolumab
  • CT-011 pidilizumab
  • AMP-224 pidilizumab
  • MDX-1105 MEDI4736
  • MPDL3280A MPDL3280A
  • BMS-936559 ipilimumab
  • lirlumab IPH2101, pembrolizumab (KEYTRUDA®)
  • tremelimumab tremelimum
  • an immune checkpoint inhibitor is REGN2810 (Regeneron), an anti-PD-1 antibody tested in patients with basal cell carcinoma (NCT03132636); NSCLC (NCT03088540); cutaneous squamous cell carcinoma (NCT02760498); lymphoma (NCT02651662); and melanoma (NCT03002376); pidilizumab (CureTech), also known as CT- 011, an antibody that binds to PD-1, in clinical trials for diffuse large B-cell lymphoma and multiple myeloma; avelumab (BAVENCIO®, Pfizer/Merck KGaA), also known as MSB0010718C), a fully human IgG1 anti-PD-L1 antibody, in clinical trials for non-small cell lung cancer, Merkel cell carcinoma, mesothelioma, solid tumors, renal cancer, ovarian cancer, bladder cancer, head and neck cancer, and gastric cancer; or P
  • Tremelimumab (CP-675,206; Astrazeneca) is a fully human monoclonal antibody against CTLA-4 that has been in studied in clinical trials for a number of indications, including: mesothelioma, colorectal cancer, kidney cancer, breast cancer, lung cancer and non-small cell lung cancer, pancreatic ductal adenocarcinoma, pancreatic cancer, germ cell cancer, squamous cell cancer of the head and neck, hepatocellular carcinoma, prostate cancer, endometrial cancer, metastatic cancer in the liver, liver cancer, large B-cell lymphoma, ovarian cancer, cervical cancer, metastatic anaplastic thyroid cancer, urothelial cancer, fallopian tube cancer, multiple myeloma, bladder cancer, soft tissue sarcoma, and melanoma.
  • AGEN-1884 (Agenus) is an anti-CTLA4 antibody that is being studied in Phase 1 clinical trials for advanced solid tumors (NCT02694822).
  • a checkpoint inhibitor is an inhibitor of T-cell immunoglobulin mucin containing protein-3 (TIM-3).
  • TIM-3 inhibitors that may be used in the present invention include TSR-022, LY3321367 and MBG453.
  • TSR-022 (Tesaro) is an anti-TIM-3 antibody which is being studied in solid tumors (NCT02817633).
  • LY3321367 (Eli Lilly) is an anti-TIM-3 antibody which is being studied in solid tumors (NCT03099109).
  • a checkpoint inhibitor is an inhibitor of T cell immunoreceptor with Ig and ITIM domains, or TIGIT, an immune receptor on certain T cells and NK cells.
  • TIGIT inhibitors that may be used in the present invention include BMS-986207 (Bristol-Myers Squibb), an anti-TIGIT monoclonal antibody (NCT02913313); OMP-313M32 (Oncomed); and anti-TIGIT monoclonal antibody (NCT03119428).
  • a checkpoint inhibitor is an inhibitor of Lymphocyte Activation Gene-3 (LAG-3).
  • LAG-3 inhibitors that may be used in the present invention include BMS- 986016 and REGN3767 and IMP321.
  • BMS-986016 (Bristol-Myers Squibb), an anti-LAG-3 antibody, is being studied in glioblastoma and gliosarcoma (NCT02658981).
  • REGN3767 (Regeneron), is also an anti-LAG-3 antibody, and is being studied in malignancies (NCT03005782).
  • IMP321 is an LAG-3-Ig fusion protein, being studied in melanoma (NCT02676869); adenocarcinoma (NCT02614833); and metastatic breast cancer (NCT00349934).
  • Checkpoint inhibitors that may be used in the present invention include OX40 agonists.
  • OX40 agonists that are being studied in clinical trials include PF-04518600/PF-8600 (Pfizer), an agonistic anti-OX40 antibody, in metastatic kidney cancer (NCT03092856) and advanced cancers and neoplasms (NCT02554812; NCT05082566); GSK3174998 (Merck), an agonistic anti-OX40 antibody, in Phase 1 cancer trials (NCT02528357); MEDI0562 (Medimmune/AstraZeneca), an agonistic anti-OX40 antibody, in advanced solid tumors (NCT02318394 and NCT02705482); MEDI6469, an agonistic anti-OX40 antibody (Medimmune/AstraZeneca), in patients with colorectal cancer (NCT02559024), breast cancer (NCT01862900), head and neck cancer (NCT02274155) and metastatic prostate cancer (NCT01303705); and BMS-986178 (Bristol- My
  • Checkpoint inhibitors that may be used in the present invention include CD137 (also called 4-1BB) agonists.
  • CD137 agonists that are being studied in clinical trials include utomilumab (PF-05082566, Pfizer) an agonistic anti-CD137 antibody, in diffuse large B-cell lymphoma (NCT02951156) and in advanced cancers and neoplasms (NCT02554812 and NCT05082566); urelumab (BMS-663513, Bristol-Myers Squibb), an agonistic anti-CD137 antibody, in melanoma and skin cancer (NCT02652455) and glioblastoma and gliosarcoma (NCT02658981); and CTX-471 (Compass Therapeutics), an agonistic anti-CD137 antibody in metastatic or locally advanced malignancies (NCT03881488).
  • Checkpoint inhibitors that may be used in the present invention include CD27 agonists.
  • CD27 agonists that are being studied in clinical trials include varlilumab (CDX-1127, Celldex Therapeutics) an agonistic anti-CD27 antibody, in squamous cell head and neck cancer, ovarian carcinoma, colorectal cancer, renal cell cancer, and glioblastoma (NCT02335918); lymphomas (NCT01460134); and glioma and astrocytoma (NCT02924038).
  • Checkpoint inhibitors that may be used in the present invention include glucocorticoid- induced tumor necrosis factor receptor (GITR) agonists.
  • GITR glucocorticoid- induced tumor necrosis factor receptor
  • GITR agonists that are being studied in clinical trials include TRX518 (Leap Therapeutics), an agonistic anti-GITR antibody, in malignant melanoma and other malignant solid tumors (NCT01239134 and NCT02628574); GWN323 (Novartis), an agonistic anti-GITR antibody, in solid tumors and lymphoma (NCT 02740270); INCAGN01876 (Incyte/Agenus), an agonistic anti-GITR antibody, in advanced cancers (NCT02697591 and NCT03126110); MK-4166 (Merck), an agonistic anti-GITR antibody, in solid tumors (NCT02132754) and MEDI1873 (Medimmune/AstraZeneca), an agonistic hexameric GITR-ligand molecule with a human IgG1 Fc domain, in advanced solid tumors (NCT02583165).
  • TRX518 Leap Therapeutics
  • Checkpoint inhibitors that may be used in the present invention include inducible T- cell co-stimulator (ICOS, also known as CD278) agonists.
  • ICOS agonists that are being studied in clinical trials include MEDI-570 (Medimmune), an agonistic anti-ICOS antibody, in lymphomas (NCT02520791); GSK3359609 (Merck), an agonistic anti-ICOS antibody, in Phase 1 (NCT02723955); JTX-2011 (Jounce Therapeutics), an agonistic anti-ICOS antibody, in Phase 1 (NCT02904226).
  • Checkpoint inhibitors that may be used in the present invention include killer IgG-like receptor (KIR) inhibitors.
  • KIR killer IgG-like receptor
  • KIR inhibitors that are being studied in clinical trials include lirilumab (IPH2102/BMS-986015, Innate Pharma/Bristol-Myers Squibb), an anti-KIR antibody, in leukemias (NCT01687387, NCT02399917, NCT02481297, NCT02599649), multiple myeloma (NCT02252263), and lymphoma (NCT01592370); IPH2101 (1-7F9, Innate Pharma) in myeloma (NCT01222286 and NCT01217203); and IPH4102 (Innate Pharma), an anti-KIR antibody that binds to three domains of the long cytoplasmic tail (KIR3DL2), in lymphoma (NCT02593045).
  • Checkpoint inhibitors that may be used in the present invention include CD47 inhibitors of interaction between CD47 and signal regulatory protein alpha (SIRPa).
  • CD47/SIRPa inhibitors that are being studied in clinical trials include ALX-148 (Alexo Therapeutics), an antagonistic variant of (SIRPa) that binds to CD47 and prevents CD47/SIRPa-mediated signaling, in phase 1 (NCT03013218); TTI-621 (SIRPa-Fc, Trillium Therapeutics), a soluble recombinant fusion protein created by linking the N-terminal CD47-binding domain of SIRPa with the Fc domain of human IgG1, acts by binding human CD47, and preventing it from delivering its “do not eat” signal to macrophages, is in clinical trials in Phase 1 (NCT02890368 and NCT02663518); CC-90002 (Celgene), an anti-CD47 antibody, in leukemias (NCT02641002); and Hu5
  • Checkpoint inhibitors that may be used in the present invention include CD73 inhibitors.
  • CD73 inhibitors that are being studied in clinical trials include MEDI9447 (Medimmune), an anti-CD73 antibody, in solid tumors (NCT02503774); and BMS-986179 (Bristol-Myers Squibb), an anti-CD73 antibody, in solid tumors (NCT02754141).
  • Checkpoint inhibitors that may be used in the present invention include agonists of stimulator of interferon genes protein (STING, also known as transmembrane protein 173, or TMEM173).
  • STING stimulator of interferon genes protein
  • Agonists of STING that are being studied in clinical trials include MK-1454 (Merck), an agonistic synthetic cyclic dinucleotide, in lymphoma (NCT03010176); and ADU- S100 (MIW815, Aduro Biotech/Novartis), an agonistic synthetic cyclic dinucleotide, in Phase 1 (NCT02675439 and NCT03172936).
  • Checkpoint inhibitors that may be used in the present invention include CSF1R inhibitors.
  • CSF1R inhibitors that are being studied in clinical trials include pexidartinib (PLX3397, Plexxikon), a CSF1R small molecule inhibitor, in colorectal cancer, pancreatic cancer, metastatic and advanced cancers (NCT02777710) and melanoma, non-small cell lung cancer, squamous cell head and neck cancer, gastrointestinal stromal tumor (GIST) and ovarian cancer (NCT02452424); and IMC-CS4 (LY3022855, Lilly), an anti-CSF-1R antibody, in pancreatic cancer (NCT03153410), melanoma (NCT03101254), and solid tumors (NCT02718911); and BLZ945 (4-[2((1R,2R)-2-hydroxycyclohexylamino)-benzothiazol-6-yloxyl]-pyridine-2- carboxylic acid methylamide, Novartis), an orally available inhibitor of CSF1R, in advanced solid tumors
  • Checkpoint inhibitors that can be used in the present invention include NKG2A receptor inhibitors.
  • NKG2A receptor inhibitors that are being studied in clinical trials include monalizumab (IPH2201, Innate Pharma), an anti-NKG2A antibody, in head and neck neoplasms (NCT02643550) and chronic lymphocytic leukemia (NCT02557516).
  • the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab, atezolizumab, or pidilizumab.
  • Step 2 [3-(Trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]methyl methanesulfonate [00410] To a solution of [3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]methanol (180 mg, 975.08 ⁇ mol, 90% purity, 1 eq) and Et 3 N (197.33 mg, 1.95 mmol, 271.44 ⁇ L, 2 eq) in DCM (3 mL) was added MsCl (170 mg, 1.48 mmol, 114.86 ⁇ L, 1.52 eq) dropwise at 0 °C and the mixture stirred at 25°C for 2 h.
  • Step 3 N-[(1R,5S)-3-[[4-(Trifluoromethyl)-1-bicyclo[2.2.2]octanyl]methyl]-3- azabicyclo[3.1.0]hexan-6-yl]prop-2-enamide [00414] To a solution of N-[(1S,5R)-3-azabicyclo[3.1.0]hexan-6-yl]prop-2-enamide (120 mg, 360.61 ⁇ mol, 80% purity, 1 eq, TFA) and TEA (36.49 mg, 360.61 ⁇ mol, 50.19 ⁇ L, 1 eq) in MeOH (10 mL) was added 4-(trifluoromethyl)bicyclo[2.2.2]octane-1-carbaldehyde (47.43 mg, 211.62 ⁇ mol, 92% purity).
  • Step 2 tert-Butyl (4-amino-2-bromophenyl)(4-(trifluoromethyl)benzyl)carbamate
  • tert-butyl N-(2-bromo-4-nitro-phenyl)-N-[[4- (trifluoromethyl)phenyl]methyl]carbamate (1.11 g, 2.31 mmol, 98.7%, 1 eq) in EtOH (5 mL) and H2O (5 mL) was added Fe (646.28 mg, 11.57 mmol, 5 eq) and NH4Cl (1.24 g, 23.15 mmol, 10 eq).
  • Step 3 tert-Butyl (4-acrylamido-2-bromophenyl)(4-(trifluoromethyl)benzyl)carbamate
  • tert-butyl N-(4-amino-2-bromo-phenyl)-N-[[4- (trifluoromethyl)phenyl]methyl]carbamate 250 mg, 539.00 ⁇ mol, 96% purity, 1 eq
  • acryloyl chloride 73.18 mg, 808.49 ⁇ mol, 65.92 ⁇ L, 1.5 eq
  • DIEA 139.32 mg, 1.08 mmol, 187.77 ⁇ L, 2 eq).
  • Step 4 tert-Butyl (4-acrylamido-2-(1-methyl-1H-imidazol-4-yl)phenyl)(4- (trifluoromethyl)benzyl)carbamate [00418] To a solution of tert-butyl N-[2-bromo-4-(prop-2-enoylamino)phenyl]-N-[[4- (trifluoromethyl)phenyl]methyl]carbamate (200 mg, 400.54 ⁇ mol, 100%, 1 eq) and tributyl-(1- methylimidazol-4-yl)stannane (234.73 mg, 600.82 ⁇ mol, 95%, 1.5 eq) in DMF (7 mL) was added Pd(dppf)Cl2 (29.31 mg, 40.05 ⁇ mol, 0.1 eq).
  • Step 5 N-(3-(1-Methyl-1H-imidazol-4-yl)-4-((4- (trifluoromethyl)benzyl)amino)phenyl)acrylamide
  • tert-butyl N-[2-(1-methylimidazol-4-yl)-4-(prop-2- enoylamino)phenyl]-N-[[4-(trifluoromethyl)phenyl]methyl]carbamate 100 mg, 199.80 ⁇ mol, 100%, 1 eq
  • TFA 3.08 g, 27.01 mmol, 2.00 mL, 135.20 eq.
  • Step 2 N-Methyl-4-[[5-(trifluoromethyl)-2-pyridyl]amino]-3-vinyl-benzenesulfonamide
  • N-[(4-methoxyphenyl)methyl]-N-methyl-4-[[5-(trifluoromethyl)-2- pyridyl]amino]-3-vinyl-benzenesulfonamide 500 mg, 1.04 mmol, 98.9% purity, 1 eq
  • TFA 1.52 g, 13.37 mmol, 989.70 ⁇ L, 12.90 eq
  • Step 3 3-[(5S)-3-Bromo-4,5-dihydroisoxazol-5-yl]-N-methyl-4-[[5-(trifluoromethyl)-2- pyridyl]amino]benzenesulfonamide and 3-[(5R)-3-bromo-4,5-dihydroisoxazol-5-yl]-N- methyl-4-[[5-(trifluoromethyl)-2-pyridyl]amino]benzenesulfonamide [00422] To a stirred solution of N-methyl-4-[[5-(trifluoromethyl)-2-pyridyl]amino]-3-vinyl- benzenesulfonamide (270 mg, 724.58 ⁇ mol, 95.9%, 1 eq) and dibromomethanone oxime (293.94 mg, 1.45 mmol, 2 eq) in EtOAc (10 mL) was added NaHCO3 (608.
  • Step 2 tert-Butyl N-(5-bromo-2-iodo-phenyl)-N-[[4- (trifluoromethyl)phenyl]methyl]carbamate
  • DMAP 448.24 mg, 3.67 mmol, 1 eq
  • Boc 2 O 2.40 g, 11.01 mmol, 2.53 mL, 3 eq
  • Step 3 tert-Butyl N-[5-bromo-2-(1-methylimidazol-4-yl)phenyl]-N-[[4- (trifluoromethyl)phenyl]methyl]carbamate [00425] A mixture of tert-butyl N-(5-bromo-2-iodo-phenyl)-N-[[4- (trifluoromethyl)phenyl]methyl]carbamate (1 g, 1.73 mmol, 96.3% purity, 1 eq), tributyl-(1- methylimidazol-4-yl)stannane (662.53 mg, 1.73 mmol, 97% purity, 1 eq) and Pd(dppf)Cl 2 (126.70 mg, 173.15 ⁇ mol, 0.1 eq) in DMF (10 mL) was degassed and purged with N 2 for 3 times and the mixture was stirred under N2 atmosphere at 120 °C for 4 h.
  • Step 4 tert-Butyl N-[2-(1-methylimidazol-4-yl)-5-vinyl-phenyl]-N-[[4- (trifluoromethyl)phenyl]methyl]carbamate
  • a mixture of tert-butyl N-[5-bromo-2-(1-methylimidazol-4-yl)phenyl]-N-[[4- (trifluoromethyl)phenyl]methyl]carbamate 530 mg, 934.66 ⁇ mol, 90%, 1 eq)
  • 4,4,5,5- tetramethyl-2-vinyl-1,3,2-dioxaborolane (287.90 mg, 1.87 mmol, 317.07 ⁇ L, 2 eq)
  • Pd(dppf)Cl2 68.39 mg, 93.47 ⁇ mol, 0.1 eq
  • Step 5 tert-Butyl N-[2-(1-methylimidazol-4-yl)-5-vinyl-phenyl]-N-[[4- (trifluoromethyl)phenyl]methyl]carbamate [00427] To a solution of tert-butyl N-[2-(1-methylimidazol-4-yl)-5-vinyl-phenyl]-N-[[4- (trifluoromethyl)phenyl]methyl]carbamate (169 mg, 358.33 ⁇ mol, 97%, 1 eq) and dibromomethanone oxime (109.02 mg, 537.49 ⁇ mol, 1.5 eq) in EtOAc (3 mL) was added NaHCO 3 (301.02 mg, 3.58 mmol, 10 eq).
  • Step 6 (S)-5-(3-Bromo-4,5-dihydroisoxazol-5-yl)-2-(1-methyl-1H-imidazol-4-yl)-N-(4- (trifluoromethyl)benzyl)aniline and (R)-5-(3-bromo-4,5-dihydroisoxazol-5-yl)-2-(1-methyl- 1H-imidazol-4-yl)-N-(4-(trifluoromethyl)benzyl)aniline
  • Step 2 2-(1-Methyl-1H-imidazol-4-yl)-N 1 -(5-(trifluoromethyl)pyridin-2-yl)benzene-1,4- diamine
  • N-(2-bromo-4-nitro-phenyl)-5-(trifluoromethyl)pyridin-2-amine 700 mg, 1.93 mmol, 1 eq
  • tributyl-(1-methylimidazol-4-yl)stannane (1.58 g, 3.87 mmol, 91%, 2 eq)
  • Pd(dppf)Cl2 70.73 mg, 96.66 ⁇ mol, 0.05 eq
  • Step 3 N-(3-(1-Methyl-1H-imidazol-4-yl)-4-((5-(trifluoromethyl)pyridin-2- yl)amino)phenyl)acrylamide
  • 2-(1-methylimidazol-4-yl)-N 1 -[5-(trifluoromethyl)-2- pyridyl]benzene-1,4-diamine 230 mg, 496.83 ⁇ mol, 72%, 1 eq
  • Et 3 N 150.82 mg, 1.49 mmol, 207.46 ⁇ L, 3 eq) in DCM (3 mL) was added prop-2-enoyl chloride (58.46 mg, 645.88 ⁇ mol, 52.66 ⁇ L, 1.3 eq) under N 2 atmosphere at 0 °C.
  • Step 2 6-Amino-5-bromo-N-[(4-methoxyphenyl)methyl]-N-methyl-pyridine-3-sulfonamide
  • NH3.H2O 950 mg, 2.15 mmol, 92% purity, 1 eq
  • THF 5 mL
  • NH3.H2O 1.48 mL, 28% purity, 5 eq
  • the mixture was stirred under microwave at 100 °C for 12 h.
  • Step 3 5-Bromo-N-[(4-methoxyphenyl)methyl]-N-methyl-6-[4- (trifluoromethyl)anilino]pyridine-3-sulfonamide
  • 6-amino-5-bromo-N-[(4-methoxyphenyl)methyl]-N-methyl-pyridine- 3-sulfonamide 510 mg, 1.25 mmol, 95% purity, 1 eq
  • 1-iodo-4-(trifluoromethyl)benzene (409.42 mg, 1.51 mmol, 221.31 ⁇ L, 1.2 eq) in anisole (20 mL) were added Pd(OAc)2 (42.24 mg, 188.15 ⁇ mol, 0.15 eq), xantphos (72.58 mg, 125.43 ⁇ mol, 0.1 eq) and Cs2CO3 (613.02 mg, 1.88 mmol, 1.5 eq).
  • Step 4 N-[(4-Methoxyphenyl)methyl]-N-methyl-6-[4-(trifluoromethyl)anilino]-5-vinyl- pyridine-3-sulfonamide
  • 5-bromo-N-[(4-methoxyphenyl)methyl]-N-methyl-6-[4- (trifluoromethyl)anilino]pyridine-3-sulfonamide 587 mg, 1.05 mmol, 95% purity, 1 eq
  • 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (323.88 mg, 2.10 mmol, 356.70 ⁇ L, 2 eq) in 1,4- dioxane (18 mL) and H2O (3 mL) were added Pd(dppf)Cl2 (76.94 mg, 105.15 ⁇ mol, 0.1 eq) and Cs 2 CO 3 (685.17 mg, 2.10
  • Step 5 N-Methyl-6-[4-(trifluoromethyl)anilino]-5-vinyl-pyridine-3-sulfonamide
  • N-[(4-methoxyphenyl)methyl]-N-methyl-6-[4- (trifluoromethyl)anilino]-5-vinyl-pyridine-3-sulfonamide 300 mg, 628.27 ⁇ mol, 100% purity, 1 eq
  • DCM 5 mL
  • TFA 1.5 mL
  • the mixture was stirred at 25 °C for 16 h.
  • Step 6 5-(3-Bromo-4,5-dihydroisoxazol-5-yl)-N-methyl-6-[4- (trifluoromethyl)anilino]pyridine-3-sulfonamide
  • N-methyl-6-[4-(trifluoromethyl)anilino]-5-vinyl-pyridine-3- sulfonamide 330 mg, 616.07 ⁇ mol, 88% purity, 1 eq, TFA
  • dibromomethanone oxime 249.92 mg, 1.23 mmol, 2 eq
  • EtOAc 20 mL
  • Step 7 (S)-5-(3-Bromo-4,5-dihydroisoxazol-5-yl)-N-methyl-6-((4- (trifluoromethyl)phenyl)amino)pyridine-3-sulfonamide
  • the compound 5-(3-bromo-4,5-dihydroisoxazol-5-yl)-N-methyl-6-[4- (trifluoromethyl)anilino]pyridine-3-sulfonamide (100 mg, 198.22 ⁇ mol, 95% purity, 1 eq) was separated by chiral SFC (column: DAICEL CHIRALPAK AD(250mm*30mm,10um);mobile phase: [0.1%NH 3 H 2 O EtOH]; B%: 30%-30%) to yield Peak 1 and Peak 2.
  • Step 1 4-Bromo-2-(1-methylimidazol-4-yl)aniline
  • 4-bromo-2-iodo-aniline (2 g, 6.71 mmol, 1 eq)
  • tributyl-(1- methylimidazol-4-yl)stannane (2.72 g, 6.71 mmol, 91.5%, 1 eq)
  • Pd(dppf)Cl 2 491.22 mg, 671.32 ⁇ mol, 0.1 eq.
  • the mixture was stirred under N 2 atmosphere at 130 °C for 12 h.
  • Step 2 2-(1-Methylimidazol-4-yl)-4-vinyl-aniline [00441] To a solution of 4-bromo-2-(1-methylimidazol-4-yl)aniline (1 g, 3.25 mmol, 82.0%, 1 eq) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.00 g, 6.51 mmol, 1.10 mL, 2 eq) in 1,4-dioxane (30 mL) and H2O (6 mL) was added Pd(dppf)Cl2 (237.99 mg, 325.25 ⁇ mol, 0.1 eq) and Cs2CO3 (3.18 g, 9.76 mmol, 3 eq).
  • Step 3 4-(3-Bromo-4,5-dihydroisoxazol-5-yl)-2-(1-methylimidazol-4-yl)aniline
  • 2-(1-methylimidazol-4-yl)-4-vinyl-aniline 500 mg, 2.16 mmol, 86.0%, 1 eq
  • EtOAc 10 mL
  • NaHCO 3 1.81 g, 21.58 mmol, 839.35 ⁇ L, 10 eq
  • dibromomethanone oxime (656.59 mg, 3.24 mmol, 1.5 eq).
  • the mixture was stirred at 25 °C for 12 h.
  • Step 4 4-[(5S)-3-Bromo-4,5-dihydroisoxazol-5-yl]-2-(1-methylimidazol-4-yl)-N-[[4- (trifluoromethyl)phenyl]methyl]aniline and 4-[(5R)-3-bromo-4,5-dihydroisoxazol-5-yl]-2-(1- methylimidazol-4-yl)-N-[[4-(trifluoromethyl)phenyl]methyl]aniline [00443] To a solution of 4-(3-bromo-4,5-dihydroisoxazol-5-yl)-2-(1-methylimidazol-4- yl)aniline (120 mg, 347.48 ⁇ mol, 93.0%, 1 eq) in THF (5 mL) was added DIEA (134.73 mg, 1.04 mmol, 181.57 ⁇ L, 3 eq) and 1-(bromomethyl)-4
  • Step 1 (S)-5-(3-Chloro-4,5-dihydroisoxazol-5-yl)-N-methyl-6-((4- (trifluoromethyl)phenyl)amino)pyridine-3-sulfonamide [00444] To a solution of 5-(3-bromo-4,5-dihydroisoxazol-5-yl)-N-methyl-6-[4- (trifluoromethyl)anilino]pyridine-3-sulfonamide (185 mg, 366.70 ⁇ mol, 95% purity, 1 eq) in 1,4- dioxane (10 mL) was added HCl (4 M, 0.5 mL).
  • Step 2 N-[(4-Methoxyphenyl)methyl]-N-methyl-6-[[5-(trifluoromethyl)-2-pyridyl]amino]-5- vinyl-pyridine-3-sulfonamide
  • N-[(4-Methoxyphenyl)methyl]-N-methyl-6-[[5-(trifluoromethyl)-2-pyridyl]amino]-5- vinyl-pyridine-3-sulfonamide 260 mg, 489.32 ⁇ mol, 100% purity, 1 eq
  • 1,4-dioxane 6 mL
  • H2O 1,4-dioxane
  • Pd(dppf)Cl2 35.80 mg, 48.93 ⁇ mol, 0.1 eq
  • Step 3 N-Methyl-6-[[5-(trifluoromethyl)-2-pyridyl]amino]-5-vinyl-pyridine-3-sulfonamide
  • N-[(4-methoxyphenyl)methyl]-N-methyl-6-[[5-(trifluoromethyl)-2- pyridyl]amino]-5-vinyl-pyridine-3-sulfonamide 200 mg, 409.62 ⁇ mol, 98% purity, 1 eq
  • TFA 1.51 g, 13.24 mmol, 980.00 ⁇ L, 32.31 eq
  • Step 4 5-[(5S)-3-Bromo-4,5-dihydroisoxazol-5-yl]-N-methyl-6-[[5-(trifluoromethyl)-2- pyridyl]amino]pyridine-3-sulfonamide and 5-[(5R)-3-bromo-4,5-dihydroisoxazol-5-yl]-N- methyl-6-[[5-(trifluoromethyl)-2-pyridyl]amino]pyridine-3-sulfonamide [00448] To a solution of N-methyl-6-[[5-(trifluoromethyl)-2-pyridyl]amino]-5-vinyl-pyridine- 3-sulfonamide (140 mg, 390.69 ⁇ mol, 1 eq) in EtOAc (10 mL) was added NaHCO 3 (328.22 mg, 3.91 mmol, 151.95 ⁇ L, 10 eq) and dibromomethanone
  • Step 2 N-Methyl-4-[[4-(trifluoromethyl)cyclohexyl]amino]-3-vinyl-benzenesulfonamide
  • 3-bromo-N-methyl-4-[[4- (trifluoromethyl)cyclohexyl]amino]benzenesulfonamide 210 mg, 441.64 ⁇ mol, 1 eq, HCl
  • 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane 102.03 mg, 662.45 ⁇ mol, 112.36 ⁇ L, 1.5 eq
  • 1,4-dioxane (6 mL) and H 2 O (2 mL) was added Pd(dppf)Cl 2 (32.31 mg, 44.16 ⁇ mol, 0.1 eq) and Cs2CO3 (359.73 mg, 1.10 mmol, 2.5 eq).
  • Step 3 3-[(5S)-3-Bromo-4,5-dihydroisoxazol-5-yl]-N-methyl-4-[[4- (trifluoromethyl)cyclohexyl]amino]benzenesulfonamide [00451] To a solution of N-methyl-4-[[4-(trifluoromethyl)cyclohexyl]amino]-3-vinyl- benzenesulfonamide (110 mg, 297.45 ⁇ mol, 1 eq) and in EtOAc (5 mL) was added dibromomethanone oxime (90.50 mg, 446.18 ⁇ mol, 1.5 eq) and NaHCO3 (249.88 mg, 2.97 mmol, 10 eq).
  • TEAD inhibition can be assayed using Hippo Pathway TEAD Reporter – MCF7 Cell Line (BPS Bioscience, Catalog #: 60618).
  • Background [00453] The Hippo pathway regulates cell proliferation and cell death. It is activated by high cell density and cell stress to stop cell proliferation and induce apoptosis.
  • the mammalian Hippo pathway comprises MST kinases and LATS kinases. When the Hippo pathway is activated, MST kinases phosphorylate LATS kinases, which phosphorylate transcriptional co-activators YAP and TAZ.
  • Unphosphorylated YAP and TAZ can translocate to the nucleus and interact with TEAD/TEF transcriptional factors to turn on cell cycle-promoting gene transcription. However, when phosphorylated, YAP and TAZ are recruited from the nucleus to the cytosol, so that the YAP and TAZ-dependent gene transcription is turned off. Dysfunction of the Hippo pathway is frequently detected in human cancer and its down-regulation correlates with the aggressive properties of cancer cells and poor prognosis.
  • the TEAD Reporter – MCF7 cell line contains the firefly luciferase gene under the control of TEAD responsive elements stably integrated into the human breast cancer cell line, MCF7.
  • Thaw Medium 1 (BPS Bioscience #60187) + 10 ⁇ g/ml of Insulin (Sigma-Aldrich # I0516): MEM medium (Hyclone #SH30024.01) supplemented with 10% FBS (Invitrogen #26140- 079), 1% non-essential amino acids (Hyclone #SH30238.01), 1 mM Na pyruvate (Hyclone #SH30239.01), 1% Penicillin/Streptomycin (Hyclone SV30010.01), plus 10 ⁇ g/ml of insulin (Sigma-Aldrich # I0516) [00458] Growth Medium 1B (BPS Bioscience #79531) + 10 ⁇ g/ml of Insulin (Sigma- Aldrich # I0516): Thaw Medium 1 (BPS Cat.
  • Cells should be grown at 37 o C with 5% CO2 using Growth Medium 1B with 10 ⁇ g/ml of Insulin. It may be necessary to adjust the percentage of CO2 in the incubator depending on the NaHCO 3 level in the basal medium.
  • Luminometer Mycoplasma testing [00464] The cell line has been screened using the PCR-based VenorGeM Mycoplasma Detection kit (Sigma-Aldrich) to confirm the absence of Mycoplasma species. Inhibition of TEAD reporter activity by activator of Hippo pathway in TEAD Reporter – MCF7 cells 1) Harvest TEAD Reporter – MCF7 cells from culture in growth medium and seed cells at a density of 35,000 cells per well into white clear-bottom 96-well microplate in 45 ⁇ l of assay medium. 2) Incubate cells at 37 o C in a CO2 incubator for overnight. 3) Dilute the activators (H 2 O 2 or okadaic acid) stock in assay medium.
  • Example 3 Mouse Pharmacokinetics Study [00466]
  • Formulated compounds are administered intravenously or orally via gavage to BALB/c mice. Typically, at 0.167, 0.5, 1, 2, 4, 6, 12, and 24 hours post-dose, blood is collected and processed to plasma by centrifugation and stored at -80 °C until analysis. Internal standard is added to each sample prior to protein precipitation with acetonitrile or TCA. The precipitates are filtered through a filter plate and the samples are analyzed by LC/MS/MS. A standard curve is prepared in plasma from typically from 1.0 ng/mL to 3000 ng/mL and processed in the same manner as the samples.
  • mice are randomized into each treatment group. NCI-H226 tumor bearing mice are treated by oral gavage with Vehicle (5%DMSO/95% PEG 400) or a TEAD inhibitor for a total of 3 administrations. 4 hours post-third administration, mice are euthanized and tumors collected for isolation of RNA for pharmacodynamic (PD) analysis. [00468] RNA is extracted from the tumors utilizing the QIAZOL (Qiagen) lysis reagent, tissues are then homogenized for 10 minutes using TissueLyser II (Qiagen).
  • QIAZOL Qiagen
  • RNA is then isolated from samples using the KingFisher Flex automated extraction system and MagMAX mirvana total RNA isolation kit. Manufacturer’s recommended protocol for high-throughput isolation of RNA from tissue samples is followed for RNA extraction.
  • Expression of the YAP/TEAD-regulated gene, CCN2 that encodes CTFG (Connective Tissue Growth Factor), and the housekeeping gene, human glyceraldehyde 3-phosphate dehydrogenase (GAPDH) are quantified by qRT-PCR analysis using the TaqMan Gene Expression Master Mix and TaqMan probes.
  • CTGF and GAPDH cycle threshold (Ct) values for tumor cDNA samples are determined, and CTGF expression is normalized to GAPDH as an internal control.
  • CTGF mRNA expression levels for each treatment group from tumor tissues are normalized to the vehicle control group.
  • an independent sample t-test is used for statistical analysis.
  • Example 5 Anti-Proliferation Assay
  • Individual cell lines are grown in medium according to supplier instructions and seeded into 96-well plates at a density that ensures logarithmic growth over 72-96 hours. TEAD inhibitor compounds are administered to cells at a top concentration of 10 ⁇ m and subsequently a 10 point 3-fold serial dilution is conducted.
  • TEAD targeting selectivity profiles of the TEAD inhibitor compounds described herein can be determined by any of the exemplary assays provided herein designed to monitor the interaction of TEAD isoforms or variants, e.g., human TEAD1 (UniProt KB ID P28347-1 (SEQ ID NO: 1)), human TEAD2 (UniProtKB ID Q15562 (SEQ ID NO: 2)), human TEAD3 (UniProtKB ID Q99594 (SEQ ID NO: 3)), and human TEAD4 (UniProtKB ID Q15561 (SEQ ID NO: 4), and YAP1 or TAZ.
  • human TEAD1 UniProt KB ID P28347-1 (SEQ ID NO: 1)
  • human TEAD2 UniProtKB ID Q15562 (SEQ ID NO: 2)
  • human TEAD3 UniProtKB ID Q99594 (SEQ ID NO: 3)
  • human TEAD4 UniProtKB ID Q15561 (SEQ ID NO: 4
  • TEAD1 UniProt KB ID P28347-1 (SEQ ID NO: 1)
  • human TEAD2 UniProtKB ID Q15562 (SEQ ID NO: 2)
  • human TEAD3 UniProtKB ID Q99594 (SEQ ID NO: 3)
  • human TEAD4 UniProtKB ID Q15561 (SEQ ID NO: 4
  • YAP1 or TAZ
  • the first exemplary assay is an in vitro biochemical fluorescent polarization assay using recombinantly expressed and purified YAP-binding domains of individual TEAD isoforms and a fluorescently labeled peptide derived from the primary sequence of YAP1.
  • Compounds are incubated with individual TEAD isoform proteins and the fluorescent peptide and potency is determined by quantifying the displacement of the peptide.
  • the second exemplary assay is a cell-based assay employing the split luciferase reporter system (Hall et al., ACS Chem. Biol.2012, 7, 11, 1848-1857, the contents of which are herein incorporated by reference in their entireties). Briefly, the YAP-binding domain of each TEAD isoform is transiently co-expressed with the TEAD-binding domain or either YAP1 or TAZ in HEK293 cells and the proximity of the two chimeric gene fusion products is monitored by luciferase activity (Nouri et al. Cancers (Basel). 2019 Oct 19;11(10), the contents of which are herein incorporated by reference in their entireties).
  • TEAD isoform decreases the resulting luciferase activity relative to vehicle treated controls.
  • YAP1 decreases the resulting luciferase activity relative to vehicle treated controls.
  • these chimeric gene fusions are recombinantly expressed in bacteria or insect cells and employed as an in vitro biochemical assay with a similar luciferase readout as the cell-based assay.
  • Another exemplary assay is a thiol conjugation assay that monitors prevention of covalent binding of a fluorescence turn-on probe to a cysteine in the central pocket of TEAD isoforms by small molecules, as described in Karatas et al., “Discovery of Covalent Inhibitors Targeting the Transcriptional Enhanced Associate Domain (TEAD) Central Pocket,” J. Med. Chem.2020, the contents of which are herein incorporated by reference in their entireties. Briefly, the thiol reactive pro-fluorescent probe, N-(4-(7-diethylamino-4-methylcoumarin-3-yl) phenyl) maleimide (CPM) is used.
  • CPM thiol reactive pro-fluorescent probe
  • CPM The fluorescence in CPM is quenched due to the maleimide substitution on the phenyl group that modulates the resonance between the coumarin carbonyl and 7-amino groups.
  • CPM fluorescence increases strongly.
  • CPM can be used to investigate TEAD inhibition because reaction of a free cysteine residue in the TEAD central pocket yields a fluorescence signal, such that small molecules that bind to the TEAD central pocket with appreciable potency prevents covalent labeling of the cysteine by CPM.
  • TEAD protein solutions are added and incubated at room temperature with test compounds in assay buffer, followed by the addition of a CPM solution and fluorescence is measured (Ex/Em: 380/470 nm).
  • CPM solution 380/470 nm
  • Any test compounds that bind the TEAD central pocket with appreciable potency show less fluorescence or inhibition of fluorescence relative to compounds that do not bind the TEAD central pocket.
  • This cell line is selected, in part, based on its mutational status and the ability of a siRNA directed against YAP, TAZ or TEAD1-TEAD4 to inhibit cell proliferation.
  • the nuclear localization of YAP at confluence is also taken into account.
  • 10,000 cells/well are plated in a 96-well black plate with clear flat bottom TC-Treated Imaging plate in regular medium with serum, which is replaced the day after with starvation medium containing 1% serum. After one day growth in the starvation medium, cells are incubated with TEAD inhibitor compounds. The starting concentration is 30 ⁇ M and serial dilutions in DMSO and medium are performed until 0.1 ⁇ M to achieve a final DMSO concentration of 0.5%.
  • the cells are then allowed to grow for 3 days, and then, EdU (Invitrogen, Molecular Probe) is added in each well at a final concentration of 10 mM and the cells are returned to the incubator for an additional 24h.
  • EdU Invitrogen, Molecular Probe
  • the starvation medium is removed and 100 ⁇ l of PFA 4% containing Hoechst dye is added in each well to fix the cells. Plates are then incubated at room temperature for 15 min, washed twice with PBS, and the cells permeabilized by adding 100 ⁇ l per well of triton-100 containing 0.3% BSA. After 20 min, cells are washed with PBS and EdU detection is performed according to the instructions of the manufacturer. Image acquisition is performed, for example, using the ImageXpress Micro and analyzed using the MetaXpress software (Molecular Device).

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