Combination of MCL-1 inhibitors and anticancer drugs

Abstract

The present disclosure relates generally to methods of treating cancer by administering an MCL-1 inhibitor and an anti-cancer agent.

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims the benefits of U.S. Provisional Application No. 63 / 209,682, filed on 11 June 2021. The contents of this application are incorporated herein by reference in their entirety.

[0002] (Field of Invention) This application generally relates to combination therapy of MCL-1 inhibitors and anticancer drugs. [Background technology]

[0003] Apoptosis (programmed cell death) is a process that removes undesirable or potentially dangerous cells from an organism. Avoiding apoptosis is important for tumor development and sustained growth. Myelocyte leukemia 1 protein (MCL-1; also abbreviated as Mcl-1 or MCL1) is an anti-apoptotic member of the Bcl-2 family of proteins. MCL-1 is overexpressed in many cancers. Overexpression of MCL-1 prevents cancer cells from undergoing apoptosis.

[0004] Research shows that various cancers can be treated using MCL-1 inhibitors.For example, see the following: “The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models”, A. Kotschy et al., Nature, 2016(538):477 - 482; “Structure Based Design of Non-Natural Peptidic Macrocyclic Mcl-1 Inhibitors”, J. Johannes et al., ACS Med.Chem.Lett., 2017, 8(2):239 - 244 & ACS Med.Chem.Lett., 2017, 8(11):1204; “Synergistic action of the MCL-1 inhibitor S63845 with current therapies in preclinical models of triple-negative and HER2-amplified breast cancer”, D. Merino et al., Sci.Transl.Med., 2017 Aug.2, 9(401):eaam7049; “Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia”, A. Tron et al., Nature Comm.2018(9):Article No.5341; “AMG 176, a Selective MCL1 Inhibitor, Is Effective in Hematologic Cancer Models Alone and in Combination with Established Therapies”, S. Caenepeel et al., Cancer Discov., 2018 Dec 8(12):1582 - 1597; “Discovery of S64315, a Potent and Selective Mcl-1 Inhibitor”, Z. Szlavik at al., J.Med.Chem., 2020, 63(22):13762 - 13795。 There remains a need to provide more effective methods for treating cancer. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] “The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models”, A. Kotschy et al., Nature, 2016(538):477-482 [Non-Patent Document 2] "Synergistic action of the MCL-1 inhibitor S63845 with current therapies in preclinical models of triple-negative and HER2-amplified breast cancer", D.Merino et al.,Sci.Transl.Med.,2017 Aug.2,9(401):eaam7049 [Non-Patent Document 3] "Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia", A. Tron et al., Nature Comm.2018(9):Article No.5341 [Non-Patent Document 4] “AMG 176,a Selective MCL1 Inhibitor,Is Effective in Hematologic Cancer Models Alone and in Combination with Established Therapies”, S.Caenepeel et al.,Cancer Discov.,2018 Dec 8(12):1582-1597 [Non-Patent Document 5] 「Discovery of S64315,a Potent and Selective Mcl-1 Inhibitor」、Z.Szlavik at al.,J.Med.Chem.,2020,63(22):13762-13795

Summary of the Invention

Means for Solving the Problems

[0006] In some embodiments, provided herein is a method of treating cancer, the method comprising administering to a human patient in need thereof a therapeutically effective amount of an anticancer agent and a therapeutically effective amount of an MCL-1 inhibitor, where the MCL-1 inhibitor is of formula (I) or a pharmaceutically acceptable salt thereof:

Chemical formula

change

change

[0007] [Figure 1] Paclitaxel therapy increases FBXW7 protein and decreases MCL1 protein and MCL1-BAK and MCL1-BIM protein dimers in TNBC cells.

[0008] [Figure 2] HCC70 inhibition and 95% CI synergistic response surface.

[0009] [Figure 3] MDA-MB-468 inhibition and 95% CI synergistic response surface.

[0010] [Figure 4] HCC1806 inhibition and 95% CI synergistic response surface

[0011] [Figure 5] TNBC PDX model CTG-1909 tumor growth.

[0012] [Figure 6] TNBC PDX model CTG-2010 tumor growth. [Modes for carrying out the invention]

[0013] definition Unless otherwise required by context, throughout this specification and the claims, the word “comprise” and its variations, such as “comprises” and “comprising,” should be interpreted in an open and comprehensive sense, that is, “includes but not limited to.”

[0014] "C u~v ", that is (C u ~C v Prefixes such as ) indicate that the following group has u to v carbon atoms, where u and v are integers. For example, "C 1~6 The term "alkyl" indicates that the alkyl group has 1 to 6 carbon atoms.

[0015] A dash ("-") that is not between two letters or symbols is used to indicate a bonding point for a substituent. For example, -C(O)NH2 is bonded via a carbon atom. Dashes at the beginning or end of a chemical group are for convenience only, and the chemical group may be shown with or without one or more dashes without losing their usual meaning. Unless chemically or structurally required, the order in which chemical groups are written or named does not indicate or imply direction.

[0016] The term "substituted" means that one or more hydrogen atoms on a hydrocarbon are substituted by one or more atoms or groups other than hydrogen, provided that the normal valence of the specified carbon atom is not exceeded. A "substituent" is the atom or group that substitutes a hydrogen atom on a hydrocarbon when it is "substituted". Unless otherwise specified, if a group is described as being optionally substituted, any substituent of the group is itself unsubstituted.

[0017] In this specification, references to values ​​or parameters "about" include (and describe) embodiments relating to the value or parameter itself. In certain embodiments, the term "about" includes the indicated amount ± 10%. In other embodiments, the term "about" includes the indicated amount ± 5%. In certain other embodiments, the term "about" includes the indicated amount ± 1%. Furthermore, "about X" for that term includes a description of "X". Also, the singular forms "a" and "the" include a plural reference unless otherwise clearly indicated in the context. Thus, for example, a reference to "compound" includes multiple such compounds, and a reference to "assay" includes a reference to one or more assays and their equivalents known to those skilled in the art.

[0018] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., C 1~20 Alkyl), having 1 to 12 carbon atoms (i.e., C 1~12 Alkyl), having 1 to 8 carbon atoms (i.e., C 1~8 Alkyl), having 1 to 6 carbon atoms (i.e., C 1~6 Alkyl), having 1 to 4 carbon atoms (i.e., C 1~4 Alkyl), having 1 to 3 carbon atoms (i.e., C 1~3 Alkyl) or having 1-2 carbon atoms (i.e., C 1~2Alkyl). Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl group having a specific number of carbon atoms is designated by a chemical name or identified by a molecular formula, all positional isomers having that number of carbon atoms can be included. For example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3), and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0019] "Aryl" refers to an aromatic carbocyclic group having a monocyclic ring (e.g., monocyclic) or a polycyclic ring including a condensed system (e.g., bicyclic or tricyclic). As used herein, aryls have 6 to 20 ring carbon atoms (i.e., C6-20 aryls), 6 to 12 carbocyclic atoms (i.e., C6-12 aryls), or 6 to 10 carbocyclic atoms (i.e., C6-10 aryls). Non-exclusive examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, and anthryl. However, aryls do not in any way encompass, and do not overlap with, heteroaryls as defined below. When one or more aryl groups are fused with a heteroaryl ring, the resulting ring system is a heteroaryl.

[0020] "Cycloalkyl" refers to saturated or partially saturated cyclic alkyl groups having monocyclic or polycyclic structures, including condensed ring systems, cross-linked ring systems, and spirocyclic systems. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0021] As used herein, "halo" or "halogen" refers to fluoro(-F), chloro(-Cl), bromo(-Br), and iodine(-I).

[0022] As used herein, the term "haloalkyl" means alkyl as defined herein, where one or more hydrogen atoms of the alkyl are independently substituted with halogen substituents that may or may not be the same. For example, C 1~6 Haloalkyl is C 1~6 It is alkyl, C 1~6 One or more hydrogen atoms of an alkyl group are substituted with a halo substituent. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, fluorochloromethyl, difluoromethyl, difluorochloromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, and pentafluoroethyl.

[0023] "Heteroaryl" refers to an aromatic group comprising an aromatic tautomer or resonance structure having a monocyclic, polycyclic, or multiple fused rings, having at least one heteroatom in the ring, i.e., one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein nitrogen or sulfur may be oxidized. Therefore, this term includes rings having one or more cyclic O, N, S, S(O), S(O)2, and N-oxide groups. This term also includes rings having one or more cyclic C(O) groups. As used herein, heteroaryl includes 5 to 20 ring atoms (i.e., 5 to 20-membered heteroaryls), 5 to 12 ring atoms (i.e., 5 to 12-membered heteroaryls), or 5 to 10 ring atoms (i.e., 5 to 10-membered heteroaryls), and 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, as well as oxidized forms of the heteroatoms. Examples of heteroaryl groups include pyridine-2(1H)-one, pyridazine-3(2H)-one, pyrimidine-4(3H)-one, quinoline-2(1H)-one, pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Heteroaryls, as defined above, do not contain an aryl group and do not overlap with aryl groups.

[0024] The terms “heterocyclyl,” “heterocyclic,” or “heterocyclic formula” refer to monoradical or diradical saturated or unsaturated groups having a monocyclic or fused ring containing one or more heteroatoms selected from nitrogen, sulfur, phosphorus, and / or oxygen within the ring. The heteroatoms in a “heterocyclyl” can be oxidized, for example, to be -N(O)-, -S(O)-, or -S(O)2-. Heterocyclyls may be monocyclic or polycyclic, and the polycyclic rings may be fused, bridging, or spiro.

[0025] "Isomers" are different compounds that have the same molecular formula. Isomers include stereoisomers, enantiomers, and diastereomers.

[0026] A "stereoisomer" refers to a compound that has the same atoms bonded together by the same bonds but has different three-dimensional structures that are not interchangeable. This disclosure intends various stereoisomers and mixtures thereof, and includes "enantiomers," which refer to two stereoisomers whose molecules are mirror images of each other and cannot be superimposed.

[0027] "Tautomerism" refers to the transfer of a proton from one atom of a molecule to another atom of the same molecule. This disclosure includes tautomers of any such compound.

[0028] A "solvate" is formed by the interaction of a solvent and a compound. Solvates of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0029] As used herein, the term "prodrug" refers to a biologically inactive derivative of a drug that, upon administration to the human body, is converted to a biologically active parent drug via several chemical or enzymatic pathways.

[0030] An "enantiomer" is a pair of stereoisomers that are mirror images of each other and cannot be superimposed. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. The symbol "(±)" is used to refer to a racemic mixture as appropriate.

[0031] A "diastelemer isomer" is a stereoisomer that has at least two chiral atoms but is not a mirror image of each other.

[0032] As used herein, “treatment” or “to treat” is an approach to obtain a beneficial or desired outcome. For the purposes of this disclosure, beneficial or desired outcomes include, but are not limited to, symptom relief and / or reduction of symptoms associated with a disease or condition. In one embodiment, “treatment” or “to treat” includes one or more of the following: a) inhibiting a disease or condition (e.g., reducing one or more symptoms resulting from a disease or condition and / or reducing the severity of a disease or condition); b) delaying or cessating the onset of one or more symptoms associated with a disease or condition (e.g., stabilizing a disease or condition, delaying the worsening or progression of a disease or condition); and c) alleviating a disease or condition, e.g., regression of clinical symptoms, improvement of a disease state, delaying disease progression, improving quality of life, and / or extending survival.

[0033] As used herein, “prevention” or “preventing” means a regimen that protects against the onset of a disease or disorder so that the clinical symptoms of the disease or disorder do not develop. Therefore, “prevention” relates to the administration of treatment to a subject before signs of the disease are detectable in the subject. The subject may be an individual at risk of developing the disease or disorder, such as an individual having one or more risk factors known to be associated with the onset or development of the disease or disorder.

[0034] As used herein, the terms “therapeutic effective dose” or “effective dose” refer to a quantity effective in eliciting a desired biological or medical response, including a sufficient amount of the drug to perform such treatment of a disease when administered to a subject for the treatment of the disease. Effective doses vary depending on the particular drug, as well as characteristics of the subject being treated, such as age and weight. Effective doses can include a range of amounts. As understood in the art, an effective dose may be one or more doses, i.e., a single dose or multiple doses may be required to achieve a desired therapeutic endpoint. Effective doses may be considered in connection with the administration of one or more therapeutic agents, and an effective dose may be considered if a single agent, when used in combination with one or more other agents, can or does achieve a desirable or beneficial outcome. The appropriate dose of any co-administered agent may be selectively reduced due to the combined effects of the agents (e.g., additive or synergistic effects).

[0035] As used herein, “concurrent administration” includes administering a unit dose of the drug disclosed herein before or after the administration of a unit dose of one or more additional therapeutic agents, for example, administering the drug disclosed herein within a few seconds, minutes, or hours of the administration of one or more additional therapeutic agents. For example, in some embodiments, a unit dose of the drug disclosed herein is administered first, followed by a unit dose of one or more additional therapeutic agents within a few seconds or minutes. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by a unit dose of the compound disclosed herein within a few seconds or minutes. In some embodiments, a unit dose of the compound disclosed herein is administered first, followed by a unit dose of one or more additional therapeutic agents several hours later (e.g., 1 to 12 hours). In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by a unit dose of the compound disclosed herein several hours later (e.g., 1 to 12 hours).

[0036] Administering one or more additional therapeutic agents "in combination" includes simultaneous (concurrent) and sequential or sequential administration in any order.

[0037] The term “simultaneously” is used herein to refer to the administration of two or more therapeutic agents, where at least a portion of the administrations overlaps in time, or where the administration of one therapeutic agent is within a short period of time relative to the administration of another therapeutic agent. For example, two or more therapeutic agents are administered within a time interval of a certain number of minutes or less.

[0038] The term “sequentially” is used herein to refer to the administration of two or more therapeutic agents in which the administration of one or more agents follows the discontinuation of the administration of one or more other agents, or in which the administration of one or more agents begins before the administration of one or more other agents. For example, two or more therapeutic agents are administered at time intervals longer than a certain number of minutes.

[0039] As used herein, “in conjunction with” refers to the administration of one therapeutic modality in addition to another therapeutic modality. Therefore, “in conjunction with” refers to the administration of one therapeutic modality before, during, or after the administration of another therapeutic modality to an individual.

[0040] The terms “conjugate” or “antibody-drug conjugate” refer to an antibody chemically linked to a second chemical part, such as a therapeutic or cytotoxic agent. The term “drug” includes chemical compounds, mixtures of chemical compounds, biological polymers, or extracts made from biological materials. In some embodiments, therapeutic or cytotoxic agents include, but are not limited to, pertussis toxin, taxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicine, doxorubicin, daunorubicin, dihydroxyanthracinedione, mitoxantrone, mitramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, and puromycin, as well as their analogues or homologs. When used in the context of immunoassays, a conjugate antibody may be a detectably labeled antibody used as the detection antibody.

[0041] "Intravenous administration" is the administration of a substance into a vein or "inside a vein." Compared to other routes of administration, intravenous (IV) routes are a faster way to deliver fluids and drugs through the body. Infusion pumps can allow for precise control over the flow rate and total volume of the drug being delivered. However, if changes in flow rate do not have serious consequences, or if a pump is unavailable, the infusion is often simply left to flow by placing the bag above the patient's height and adjusting the rate using a clamp. Alternatively, if the patient requires a high flow rate and the IV access device is large enough in diameter to accommodate it, a rapid infuser can be used. This is either an inflatable cuff placed around the fluid bag to infuse the fluid into the patient, or a similar electrical device that can also heat the fluid being infused. If the patient only needs the drug at specific times, intermittent infusion is used, which does not require additional fluid. This can use the same techniques as intravenous infusion (pump or gravity infusion), but the tube is disconnected from the IV access device after the full dose of the drug has been given. Some drugs are also given by IV push or bolus. In other words, a syringe is connected to an IV access device, and the drug is injected directly (or slowly, if it stimulates the vein or causes a rapid effect). Once the drug is injected into the fluid flow of the IV tube, there must be some means to ensure that it reaches the patient through the tube. Typically, this is achieved by allowing the fluid flow to proceed normally, thereby carrying the drug into the bloodstream. However, a second fluid injection may be used as a "flush" after the initial injection to get the drug into the bloodstream more quickly. Thus, in one embodiment, the drug(s) or combination of drugs described herein may be administered by IV, either alone or in combination with the administration of certain components of a therapeutic regimen via oral or parenteral routes.

[0042] "Oral administration" refers to a route of administration in which a substance is taken in through the mouth, and includes buccal, sublabial, and sublingual administration, as well as enteral and airway administration, unless the drug is administered via a tube, for example, so as not to come into direct contact with any part of the oral mucosa. Typical forms for oral administration of therapeutic agents include the use of tablets or capsules. Thus, in one embodiment, the compound(s) or combination of compounds described herein may be administered orally, either alone or in combination with the administration of specific components of a therapeutic regimen via an IV or parenteral route.

[0043] This specification also provides pharmaceutically acceptable salts, hydrates, solvates, tautomers, polymorphs, and prodrugs of the compound of formula (I) described herein. "pharmaceutically acceptable" or "physiologically acceptable" means a compound, salt, composition, dosage form, and other material suitable for human medicinal use.

[0044] Compounds of formula (I) described herein may be prepared and / or formulated as pharmaceutically acceptable salts. A pharmaceutically acceptable salt is a non-toxic salt of the free base form of a compound having the desired pharmacological activity of the free base. These salts may be derived from inorganic or organic acids or inorganic or organic bases. For example, a compound containing basic nitrogen may be prepared as a pharmaceutically acceptable salt by contacting the compound with an inorganic or organic acid. Non-limiting examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propioates, oxalates, malons, succinates, suberates, sebacinates, fumarates, maleates, butin-1,4-diates, and hexyl Examples include 1,6-diates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methylsulfonates, propylsulfonates, besilates, xylenesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates, and mandelates. A list of other suitable pharmaceutically acceptable salts can be found in Remington: The Science and Practice of Pharmacy, 21 st It can be found in Edition, Lippincott Williams and Wilkins, Philadelphia, Pa., 2006.

[0045] Non-limiting examples of “pharmaceutically acceptable salts” of the compounds of formula (I) disclosed herein also include alkali metals (e.g., sodium, potassium), alkaline earth metals (e.g., magnesium), ammonium, and NX4 +This includes salts derived from appropriate bases, such as (wherein X is a C1-C4 alkyl group). Examples include base addition salts such as sodium or potassium salts. MCL-1 inhibitors compound

[0046] In some embodiments, methods for treating cancer are provided herein, comprising administering a therapeutically effective dose of an anticancer agent and a therapeutically effective dose of an MCL-1 inhibitor to a human patient in need. MCL-1 inhibitors are those of formula (I) or pharmaceutically acceptable salts thereof: [ka] In the formula, R 1 It is a 5- to 10-membered heteroaryl compound containing 1-2 heteroatoms; each heteroatom is independently selected from nitrogen, sulfur, and oxygen; R 1 5-10 member heteroaryls are halo, hydroxyl, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, -OR 7 , and C 3~6 They are optionally substituted with 1 to 3 substituents independently selected from the cycloalkyl group; Each R 2 , R 3 , R 4 and R 5 These are, independently, hydrogen or C 1~6 It is alkyl; R 6 is hydrogen or halo; R 7 Hydrogen and C are independent of each other. 1~6 Alkyl, C 2~6 Alkenyl and C 3~10 It is a cycloalkyl group.

[0047] In some embodiments of the methods described herein, the MCL-1 inhibitor is a compound of formula (II) or a pharmaceutically acceptable salt thereof: [ka] Each R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 The methods defined above or elsewhere in this disclosure are provided herein.

[0048] In some embodiments, the MCL-1 inhibitor is a compound of formula (III), [ka] or a pharmaceutically acceptable salt thereof:

[0049] In some embodiments, the MCL-1 inhibitor is a compound of formula (I), formula (II), or formula (III) or a pharmaceutically acceptable salt thereof, R 2 is hydrogen. In some embodiments, R 2 C 1~3 It is alkyl. 2 It is methyl.

[0050] In some embodiments, the MCL-1 inhibitor is a compound of formula (I), formula (II), or formula (III) or a pharmaceutically acceptable salt thereof, R 3 is C 1~3 It is alkyl. In some embodiments, R 3 It is methyl.

[0051] In some embodiments, the MCL-1 inhibitor is a compound of formula (I), formula (II), or formula (III) or a pharmaceutically acceptable salt thereof, R 4 is hydrogen. In some embodiments, R 5 C 1~3 It is alkyl. In some embodiments, R 5 is methyl. In some embodiments, R 6 It is Cl.

[0052] In some embodiments, the MCL-1 inhibitor is a compound of formula (I), formula (II), or formula (III) or a pharmaceutically acceptable salt thereof, R 1 is C 1~4 Alkyl and C 1~4 Optionally substituted with alkoxyl [ka] In some embodiments, R 1 is optionally substituted with -CH3 and -OCH3. [ka] In some embodiments, R 1 is substituted with -CH3 and -OCH3 [ka] In some embodiments, R 1 teeth [ka] That is the case.

[0053] In some embodiments, the MCL-1 inhibitor is compound A, N-[(4S,7aR,9aR,10S,11E,14S)-6-chloro-10-methoxy-14-methyl-16-oxide-18-oxo-3',4',7,7a,8,9,9a,10,13,14,15,18-dodecahydro-2'H-spiro[1,19-(ethanediylidene)-16λ 4 -Cyclobuta[i][1,4]oxazepino[3,4-f][1,2,7]thiadiazacyclohexadecin-4,1'-naphthalene]-16-yl]-3-methoxy-1-methyl-1H-pyrazole-4-carboxamide, which has the following structure: [ka] Compound A is described in USPN 10,703,733 and Example 154 of WO2019 / 222112, which are incorporated herein by reference.

[0054] In some embodiments, MCL-1 inhibitors that can be administered include U.S. Patent No. 10,703,733 (Gilead Sciences), AMG-397, AMG-176, PRT-1419, S64315, AZD59991, ABBV-467, International Publication No. 2019222112 (Gilead Sciences), and International Publication No. 2021096860 (Gilead Sciences).2017147410 (Amgen), 2019046150 (Amgen), 2019036575 (Amgen), 2021021259 (Amgen), 2019173181 (Amgen), No. 2018183418 (Amgen), No. 2016033486 (Amgen), No. 2018178226 (AstraZeneca), No. 2017182625 (AstraZeneca), No. 2018178227 (AstraZene) ca), 2020099470 (AstraZeneca), 2019211721 (AstraZeneca), 2020097577 (Prelude), 2020123994 (Prelude), 2008104386 (AbbVie), No. 2008104385 (AbbVie), No. 2008131000 (AbbVie), No. 2008130970 (AbbVie), No. 2019035911 (AbbVie), No. 2019035927 (AbbVie) ), 2019035899 (AbbVie), 2010049816 (Servier), 2020160157 (Servier), 2020115183 (Servier), 2020099542 (Servier), No. 2015097123 (Servier), No. 2018078064 (Servier), No. 2020254299 (Servier), No. 2018127575 (Servier), No. 2018234433 (Servier), No. 0 Examples of compounds disclosed in Patent No. 18015526 (Servier), No. 2016207225 (Servier), No. 2020078875 (Servier), No. 2017125224 (Servier), No. 2020236817 (Servier), No. 2016207226 (Servier), No. 2016207217 (Servier), No. 2016207216 (Servier), and No. 2007147613 (Novartis) include, but are not limited to, those disclosed.

[0055] In some embodiments, the MCL-1 inhibitor is selected from AMG-397, AMG-176, PRT-1419, and S64315. In some embodiments, the MCL-1 inhibitor is AMG-176. In some embodiments, the MCL-1 inhibitor is AMG-397. In some embodiments, the MCL-1 inhibitor is PRT-1419. In some embodiments, the MCL-1 inhibitor is S64315.

[0056] The compounds disclosed herein may contain one or more chiral centers, and thus may give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined as (R)- or (S)- with respect to absolute stereochemistry. This disclosure includes all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), or (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or may be decomposed using conventional techniques, e.g., chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors, or decomposition of racemic compounds (or racemic compounds of salts or derivatives) using, for example, chiral high-pressure liquid chromatography (HPLC). Similarly, all tautomeric forms are also intended to be included. formulation

[0057] In the methods provided herein, MCL-1 inhibitors can be administered as pharmaceutical compositions. In certain embodiments, the pharmaceutical composition comprises a compound of formula (I), (II), (III) or compound A, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises one or more additional therapeutic agents, as fully described below.

[0058] The pharmaceutical composition containing the MCL-1 inhibitor disclosed in this specification, or a pharmaceutically acceptable salt thereof, may be prepared using one or more pharmaceutically acceptable excipients that can be selected according to normal conventions. "Pharmaceutically acceptable excipients" include, but are not limited to, any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifying agent that is recognized by the US Food and Drug Administration as being acceptable for use in humans or livestock.

[0059] In certain embodiments, the pharmaceutical composition is provided as a solid dosage form including a solid oral dosage form such as a tablet. The tablet may contain excipients including lubricants, fillers, binders, etc. The aqueous composition can be prepared in a sterile form and may generally be isotonic if delivery other than oral administration is intended. All compositions may contain excipients such as those described in Rowe et al, Handbook of Pharmaceutical Excipients, 6 th edition, American Pharmacists Association, 2009. The excipients can include carbohydrates such as ascorbic acid and other antioxidants, chelating agents such as EDTA, dextrin, hydroxyalkyl cellulose, hydroxyalkyl methyl cellulose, stearic acid, etc.

[0060] The pharmaceutical compositions disclosed herein include those suitable for various routes of administration including oral administration. The compositions may be presented in unit dosage form and may be prepared by any of the methods known in the pharmaceutical art. Such methods include the step of associating the active ingredient (e.g., the compound of the present disclosure or its pharmaceutically acceptable salt) with one or more pharmaceutically acceptable excipients. The compositions may be prepared by uniformly and intimately associating the active ingredient with a liquid excipient or a finely divided solid excipient or both, and then shaping the product as required. The techniques and formulations are generally described in Remington: The Science and Practice of Pharmacy, 21 stSeen in Edition, Lippincott Williams and Wilkins, Philadelphia, Pa., 2006.

[0061] The compositions described herein, suitable for oral administration, may be presented as separate units (unit dosage forms), including but not limited to capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient. In one embodiment, the pharmaceutical composition is a tablet.

[0062] In some embodiments, the tablets contain compound A at strengths of 5 mg and 25 mg. In some embodiments, the tablets contain copovidone, lactose monohydrate, microcrystalline cellulose, crospovidone, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, and talc. Antibody-drug conjugates (ADCs)

[0063] In some embodiments, the methods for treating cancer disclosed herein include administering a therapeutically effective dose of an anticancer drug, a therapeutically effective dose of an MCL-1 inhibitor, and a therapeutically effective dose of an antibody-drug conjugate to a human patient in need. In some embodiments, the antibody-drug conjugate comprises an anti-Trop-2 antibody and an anticancer drug.

[0064] In some embodiments, the antibody-drug conjugate is sacituzumab govitecan as disclosed in U.S. Patent No. 7,999,083. In some embodiments, the ADC comprises the antibody-drug conjugate disclosed in U.S. Patent No. 7,999,083, which is incorporated herein by reference. In some embodiments, the sacituzumab govitecan is sacituzumab govitecan-hziy.

[0065] In some embodiments, the anti-Trop-2 antibody-drug conjugate is datopotamab deruxtecan. In some embodiments, the anti-Trop-2 antibody-drug conjugate that can be administered includes, but is not limited to, the conjugates disclosed in U.S. Patent No. 9,850,312, International Publication No. 20240467, and International Publication No. 18036438.

[0066] In some embodiments, the antibody portion of the ADC is an IgG antibody or an antigen-binding antibody fragment. The antibody may contain various isotypes, preferably human IgG1, IgG2, IgG3, or IgG4, more preferably human IgG1 hinge and constant region sequences. The antibody or fragment may be a human-mouse chimera, a human-primate chimera, humanized (human framework and mouse hypervariable (CDR) region), or fully human antibody 60, as well as variations thereof, such as a half-IgG4 antibody (referred to as a "unibody") (as described in van der Neut Kolfschoten et al. (Science 2007;317:1554-1557)). More preferably, the antibody or fragment may be designed or selected to contain a human constant region 65 sequence belonging to a particular allotype, which may result in reduced immunogenicity when the antibody or ADC is administered to a human subject. Preferred allotypes for administration include non-Glml allotypes (nGlml), such as Glm3, Glm3,1, Glm3,2, or Glm3,1,2. More preferably, the allotype is selected from the group consisting of nGlml, Glm3, nGlml,2, and Km3 allotypes.

[0067] In some embodiments, the antibody portion of the ADC is an anti-Trop-2 antibody.In some embodiments, the anti-Trop-2 antibody used includes TROP2-XPAT (Amunix), BAT-8003 (Bio-Thera Solutions), TROP-2-IR700 (Chiome Bioscience), datopotamab deruxtecan (Daiichi Sankyo, AstraZeneca), GQ-1003 (Genequantum Healthcare, Samsung BioLogics), DAC-002 (Hangzhou DAC Biotech, Shanghai Junshi Biosciences), sacituzumab govitecan (Gilead Sciences), E1-3s (Immunomedics / Gilead, IBC Pharmaceuticals), TROP2-TRACTr (Janux Therapeutics), and LIV-2008 (LivTech / Chiome, Yakult Honsha, Shanghai Henlius). BioTech), LIV-2008b (LivTech / Chiome), anti-TROP-2a (Oncoxx), anti-TROP-2b (Oncoxx), OXG-64 (Oncoxx), OXS-55 (Oncoxx), humanized anti-Trop2-SN38 antibody conjugate (Shanghai Escugen Biotechnology, TOT Biopharma), anti-Trop2 antibody-CLB-SN-38 conjugate (Shanghai Fudan-Zhangjiang Bio-Pharmaceutical), SKB-264 (Sichuan Kelun Pharmaceutical / Klus Pharma), TROP2-Ab8 (Abmart), Trop2-IgG (Nanjing Medical University (NMU)), 90Y-DTPA-AF650 (Peking University First Hospital), hRS7-CM (SynAffix), 89Zr-DFO-AF650 (University of Examples include, but are not limited to, Wisconsin-Madison, anti-Trop2 antibody (Mediterranea Theranostic, LegoChem Biosciences), and KD-065 (Nanjing KAEDI Biotech).

[0068] Further examples of anti-TROP-2 therapies include, but are not limited to, E1.BB.3z-92MI (Immunomedics / Gilead), anti-Trop-2 CAR-T (Gilead), Trop-2CAR-T (Hangzhou Lonzyme Biological Technology), ARB-001 (Arbele), and MT-103 (Myeloid Therapeutics).

[0069] Examples of anti-TROP-2 antibodies include International Publication No. 2020016662 (Abmart), International Publication No. 2020249063 (Bio-Thera Solutions), U.S. Patent Application Publication No. 20190048095 (Bio-Thera Solutions), International Publication No. 2013077458 (LivTech / Chiome), European Patent No. 20110783675 (Chiome), International Publication No. 2015098099 (Daiichi Sankyo), International Publication No. 2017002776 (Daiichi Sankyo), International Publication No. 2020130125 (Daiichi Sankyo), International Publication No. 2020240467 (Daiichi Sankyo), U.S. Patent Application Publication No. 2021093730 (Daiichi Sankyo), and U.S. Patent No. 9850312 (DaiichiSankyo, Chinese Patent No. 112321715 (Biosion), US Patent Application Publication No. 2006193865 (Immunomedics / Gilead), International Publication No. 2011068845 (Immunomedics / Gilead), US Patent Application Publication No. 2016296633 (Immunomedics / Gilead), US Patent Application Publication No. 2017021017 (Immunomedics / Gilead), US Patent Application Publication No. 2017209594 Publication No. (Immunomedics / Gilead), No. 2017274093 (Immunomedics / Gilead), No. 2018110772 (Immunomedics / Gilead), No. 2018185351 (Immunomedics / Gilead), No. 2018271992 (Immunomedics / Gilead), International Publication No. 2018217227 (Immunomedics / Gilead), US National Patent Application Publication No. 2019248917 (Immunomedics / Gilead), Chinese Patent No. 111534585 (Immunomedics / Gilead), US Patent Application Publication No. 2021093730 (Immunomedics / Gilead), US Patent No. 2021069343 (Immunomedics / Gilead), US Patent No. 8435539 (Immunomedics / Gilead), US Patent No. 8435529 (I Immunomedics / Gilead), Patent No. 9492566 (Immunomedics / Gilead), International Publication No. 2003074566 (Gilead), International Publication No. 2020257648 (Gilead), U.S. Patent Application Publication No. 2013039861 (Gilead), International Publication No. 2014163684 (Gilead), U.S. Patent No. 9427464 (LivTech / Chiome), U.S. Patent No. 10501555 (Abruzzo Examples include, but are not limited to, those described in Theranostic / Oncoxx, International Publication No. 2018036428 (Sichuan Kelun Pharma), International Publication No. 2013068946 (Pfizer), International Publication No. 2007095749 (Roche), and International Publication No. 2020094670 (SynAffix).

[0070] Further examples of anti-TROP-2 therapeutics include, but are not limited to, those described in International Publication No. 2016201300 (Gilead) and Chinese Patent No. 108440674 (Hangzhou Lonzyme Biological Technology).

[0071] In some embodiments, the anti-Trop-2 antibody is selected from hRS7, Trop-2-XPAT, and BAT-8003.

[0072] In some embodiments, the anti-Trop-2 antibody is hRS7. In some embodiments, hRS7 is as disclosed in U.S. Patents 7,238,785, 7,517,964 and 8,084,583, which are incorporated herein by reference.

[0073] In some embodiments, the antibody-drug conjugate comprises an anti-Trop-2 antibody and an anticancer drug conjugated by a linker. In some embodiments, the linker is the linker disclosed in U.S. Patent No. 7,999,083. In some embodiments, the linker is CL2A.

[0074] In some embodiments, the drug portion of the antibody-drug conjugate is a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is selected from doxorubicin (DOX), epirubicin, morpholinodoxorubicin (morpholino-DOX), cyanomorpholino-doxorubicin (cyanomorpholino-DOX), 2-pyrrolino-doxorubicin (2-PDOX), CPT, 10-hydroxycamptothecin, SN-38, topotecan, ruthecan, 9-aminocamptothecin, 9-nitrocamptothecin, taxane, geldamycin, ansamycin, and epotilon. In some embodiments, the chemotherapeutic portion is SN-38. formulation

[0075] Appropriate routes of administration for ADCs include, but are not limited to, oral, parenteral, subcutaneous, rectal, mucosal, intestinal, intramuscular, intramedullary, intrathecal, direct intraventricular, intravenous, intravitreous, intraperitoneal, intranasal, or intraocular injection. Alternatively, the compound may be administered locally rather than systemically, for example, by direct injection of the compound into a solid tumor.

[0076] ADCs can be formulated according to known methods for preparing pharmaceutically useful compositions, thereby combining the ADC with pharmaceutically suitable excipients in a mixture. ADCs can be formulated for intravenous administration, for example, by bolus injection, slow infusion, or continuous infusion. In some embodiments, the antibody is infused over a period of less than approximately 4 hours. In some embodiments, the antibody is infused over a period of less than approximately 3 hours. For example, the first 25-50 mg may be infused within 30 minutes or 15 minutes, with the remainder infused over the next 2-3 hours. Injectable formulations can be provided in unit dosage forms, for example, in ampoules or multi-dose containers, with preservatives added. Compositions may take the form of suspensions, solutions, or emulsions in oily or aqueous media and may contain formulations such as suspending agents, stabilizers, and / or dispersants. Alternatively, the active ingredient may be in powder form for use with a suitable vehicle, such as pyrogenically decontaminated distilled water. Treatment method

[0077] In some embodiments, this disclosure provides combinations of MCL-1 and anticancer agents for treating cancer. In some embodiments, the MCL-1 inhibitor is compound A.

[0078] In some embodiments, the cancer is a Trop-2 expressing cancer.

[0079] In some embodiments, cancer is a solid tumor. In some embodiments, cancer is a solid malignant tumor. In some embodiments, cancer is a progressive solid malignant tumor.

[0080] In some embodiments, the cancer is selected from breast cancer, cervical cancer, colorectal cancer, endometrial cancer, epithelial ovarian cancer, esophageal cancer, follicular thyroid cancer, gastric cancer or gastroesophageal junction adenocarcinoma, head and neck cancer, lung cancer, hepatocellular carcinoma, non-small cell lung cancer, ovarian cancer, prostate cancer, renal cell carcinoma, small cell lung cancer, urothelial carcinoma, and urinary tract cancer.

[0081] In some embodiments, the cancer is selected from triple-negative breast cancer (TNBC), HR+ / HER2- breast cancer, urothelial carcinoma, non-squamous non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), head and neck squamous cell carcinoma (HNSCC), and muscle-invasive bladder cancer (MIBC).

[0082] In some embodiments, the cancer is metastatic. In some embodiments, the cancer is refractory.

[0083] In some embodiments, the cancer is selected from metastatic non-squamous non-small cell lung cancer (mNSCLC), metastatic triple-negative breast cancer (mTNBC), and metastatic soft tissue sarcoma with nonspecific histology.

[0084] In some embodiments, the cancer is metastatic non-squamous non-small cell lung cancer (mNSCLC). In some embodiments, the cancer is metastatic triple-negative breast cancer (mTNBC). In some embodiments, the cancer is metastatic soft tissue sarcoma with nonspecific histology.

[0085] In some embodiments, the human patient has received at least one other therapy prior to treatment with combination therapy of an MCL-1 inhibitor and an anti-cancer conjugate. In some embodiments, the human patient is one who has failed other therapies prior to the treatment disclosed herein. In some embodiments, the human patient is one who has failed one course of chemotherapy.

[0086] In some embodiments, the human patient is one who has failed therapy with an anti-PD1 agent or an anti-PDL1 agent prior to treatment with combination therapy of an MCL-1 inhibitor and an anticancer drug.

[0087] In some embodiments, the MCL-1 inhibitor and the anticancer agent are administered simultaneously or separately.

[0088] In some embodiments, the MCL-1 inhibitor is compound A. Generally, the dose of compound A administered to humans will vary depending on factors such as the patient's age, weight, height, sex, overall medical condition, and medical history. It may be desirable to provide the recipient with an antibody-conjugate dose ranging from approximately 1 mg / kg to 24 mg / kg as a single intravenous infusion, but lower or higher doses may be administered depending on the situation. For example, a dose of 1-20 mg / kg for a 70 kg patient is 70-1,400 mg. The dose may be repeated as needed, for example, once a week for 4-10 weeks, once a week for 8 weeks, or once a week for 4 weeks. In maintenance therapy, the frequency may be reduced as needed, for example, every few months, or monthly or quarterly for several months. In some embodiments, the dosage may be 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, 20 mg / kg, 22 mg / kg, 24 mg / kg, 26 mg / kg, 28 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, or 55 mg / kg. Examples of dosages include, but are not limited to, 65 mg / kg, 70 mg / kg, 80 mg / kg, 90 mg / kg, 100 mg / kg, 120 mg / kg, 140 mg / kg, 150 mg / kg, 160 mg / kg, 180 mg / kg, 200 mg / kg, 220 mg / kg, 240 mg / kg, 250 mg / kg, 260 mg / kg, 280 mg / kg, 300 mg / kg, 350 mg / kg, 400 mg / kg, 450 mg / kg, 550 mg / kg, 600 mg / kg, 650 mg / kg, 700 mg / kg, 750 mg / kg, and 800 mg / kg. Any amount in the range of 1 to 300 mg / kg may be used. Any amount in the range of 1 to 100 mg / kg may be used. In some embodiments, the dosage is administered multiple times, once or twice a week.In some embodiments, the dosage may be set using a minimum dosing schedule of 4 weeks, 8 weeks, 16 weeks, or longer. The dosing schedule may include one or two weekly doses in a cycle selected from the group consisting of (i) weekly, (ii) every other week, (iii) 1 week of treatment followed by 2, 3, or 4 weeks of rest, (iv) 2 weeks of treatment followed by 1, 2, 3, or 4 weeks of rest, (v) 3 weeks of treatment followed by 1, 2, 3, 4, or 5 weeks of rest, (vi) 4 weeks of treatment followed by 1, 2, 3, 4, or 5 weeks of rest, (vii) 5 weeks of treatment followed by 1, 2, 3, 4, or 5 weeks of rest; and (viii) monthly. The cycle may be repeated 4, 6, 8, 10, 12, 16, or 20 or more times.

[0089] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered orally.

[0090] In some embodiments, the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in doses of approximately 5 mg / kg, 15 mg / kg, or 50 mg / kg.

[0091] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 5 mg / kg.

[0092] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a 21-day cycle with a 2-day dose followed by a 5-day rest period.

[0093] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered on days 1, 2, 8, 9, 15, and 16 of each 21-day cycle for up to 105 weeks.

[0094] In some embodiments, anticancer drugs are administered by intravenous infusion.

[0095] Generally, the dosage of anticancer drugs administered to humans will vary depending on factors such as the patient's age, weight, height, sex, overall medical condition, and medical history. While it may be desirable to provide recipients with antibody-conjugate doses ranging from approximately 1 mg / kg to 24 mg / kg as a single intravenous infusion, lower or higher doses may be administered depending on the situation. For example, a dose of 1-20 mg / kg for a 70 kg patient is 70-1,400 mg. The dosage can be repeated as needed, for example, once a week for 4-10 weeks, once a week for 8 weeks, or once a week for 4 weeks. In maintenance therapy, the frequency may be reduced as needed, for example, every few months, or monthly or quarterly for several months. In some embodiments, the dosage includes, but is not limited to, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, 20 mg / kg, 22 mg / kg, and 24 mg / kg. Any amount in the range of 1 to 24 mg / kg may be used. In some embodiments, the dosage is administered multiple times, once or twice a week. Minimum dosing schedules of 4 weeks, 8 weeks, 16 weeks, or longer may be used. The administration schedule may include one or two doses per week in a cycle selected from the group consisting of (i) weekly, (ii) every other week, (iii) one week of treatment followed by two, three, or four weeks of rest, (iv) two weeks of treatment followed by one, two, three, or four weeks of rest, (v) three weeks of treatment followed by one, two, three, four, or five weeks of rest, (vi) four weeks of treatment followed by one, two, three, four, or five weeks of rest, (vii) five weeks of treatment followed by one, two, three, four, or five weeks of rest; and (viii) monthly. The cycle may be repeated four, six, eight, ten, twelve, sixteen, or twenty or more times.

[0096] In some embodiments, the anticancer drug may be administered once every two or three weeks, repeated for a total of at least three doses. Alternatively, it may be administered twice a week for four to six weeks, with a dose of approximately 200-300 mg / m². 2 If the dose can be reduced to (340 mg for a 1.7 m patient, or 4.9 mg / kg for a 70 kg patient), it may be administered once or even twice a week for 4 to 10 weeks. In some embodiments, the dosage schedule may be shortened, i.e., every 2 or 3 weeks for 2 to 3 months. However, it has been determined that higher doses, such as 2 mg / kg once a week or once every 2 to 3 weeks, can be administered by slow intravenous infusion in repeated dosing cycles. The dosing schedule can be optionally repeated at other intervals, and the dose may be administered by various parenteral routes, with appropriate adjustment of dose and schedule. In some embodiments, the dose is administered on day 1 and day 8 of each 21-day cycle.

[0097] In some embodiments, the methods disclosed herein include further administration of an antibody-drug conjugate in doses of about 4 mg / kg to about 12 mg / kg. In some embodiments, the antibody-drug conjugate is administered in doses of about 8 mg / kg to about 12 mg / kg. In some embodiments, the antibody-drug conjugate is administered in doses of about 8 mg / kg, about 10 mg / kg, or about 12 mg / kg. In some embodiments, the antibody-drug conjugate is sacituzumab govitecan.

[0098] In some embodiments, the method further includes one or more additional therapeutic modalities selected from antibodies, conjugates, gene therapy, chemotherapy, radiotherapy, surgery, BTK inhibitors, and checkpoint inhibitors.

[0099] In some embodiments, the method further includes radiotherapy.

[0100] In some embodiments, the anticancer agent is selected from chemotherapeutic agents, checkpoint inhibitors, FLT3 agonists, and BTK inhibitors.

[0101] In some embodiments, the FLT3 inhibitor is GS-3583. FLT3 agonists also include CDX-301 and the agents disclosed in PCT Publication No. 2020 / 263830.

[0102] In some embodiments, the FLT3 agonist is an Fc fusion protein disclosed in International Publication No. 2022 / 031876.

[0103] In some embodiments, the present disclosure provides a method for treating cancer. The method comprises administering an MCL-1 inhibitor and a chemotherapeutic agent for the treatment of cancer; the method further comprises administering one or more additional therapeutic agents, provided that the additional therapeutic agents are not FLT3 agonists. In some embodiments, the additional therapeutic agent is not an FLT3-Fc fusion protein. In some embodiments, the antibody-drug conjugate is sacituzumab govitecan and the MCL-1 inhibitor is compound A; the additional therapeutic agent is not an FLT3 agonist. In some embodiments, the additional therapeutic agent is not an FLT3 agonist disclosed in International Publication No. 2020 / 263830. In some embodiments, the additional therapeutic agent is not a fusion protein comprising the amino acid sequence of Sequence ID No. 14 of U.S. Patent No. 11 / 124,582.

[0104] In some embodiments, the checkpoint inhibitor is selected from anti-PD-1 agents, anti-PD-L1 agents, anti-PD-1 / PD-L1 interaction inhibitors, anti-CTLA4 agents, and anti-TIGIT agents.

[0105] In some embodiments, the checkpoint inhibitor is selected from anti-PD-1 agents, anti-PD-L1 agents, anti-PD-1 / PD-L1 interaction inhibitors, anti-CTLA4 agents, and anti-TIGIT agents. In some embodiments, the checkpoint inhibitor is selected from nivolumab, pembrolizumab, atezolizumab, dimbellimab, and pizilizumab. In some embodiments, the checkpoint inhibitor is selected from ipilimumab, lambrolizumab, tremelimumab, durvalumab, avelumab, donbanarimab, and tiragolumab.

[0106] Examples of CTLA4 inhibitors that can be co-administered include ipilimumab, tremelimumab, BMS-986218, AGEN1181, AGEN1884, BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002, BCD-145, APL-509, JS-007, BA-3071, ONC-392, AGEN-2041, JHL-1155, KN-044, CG-0161, ATOR-1144, and PBI. Examples include, but are not limited to, -5D3H5, BPI-002, and the multispecific inhibitors FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), MEDI-5752 (CTLA4 / PD-1), XmAb-20717 (PD-1 / CTLA4), and AK-104 (CTLA4 / PD-1).

[0107] Examples of PD-L1 (CD274) or PD-1 (PDCD1) inhibitors that can be administered concurrently include pembrolizumab, nivolumab, semiprimab, pizilizumab, AMP-224, MEDI0680 (AMP-514), spartalizumab, atezolizumab, avelumab, durvalumab, ALN-PDL, BMS-936559, CK-301, PF-06801591, BGB-108, BGB-A317 (tislerizumab), GLS-010 (WBP-3055), AK-103 (HX-008), GB-226, AK-105, CS-1003, HLX-10, MGA-012, BI-754091, PDR-001, AGEN-2034, JS-001 (Tripalimab), JNJ-63723283, Genolimuzumab (CBT-501), LZM-009, BCD-100, LY-3300054, SHR-1201, SHR-1210 (Camrelizumab), Sym-021, ABBV-181, PD1-PIK, BAT-1306, RO-6084 (PD-L1 Antisense Oligonucleotide), STI-1110, GX-P2, RG-7446, mDX-400, (MSB0010718C) CX-072, CBT-502, TSR-042 (dostallimab), MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155), MEDI-0680, emvafolimab (KN-035), KD-033, KY-1003, IBI-308 (sintilimab), HLX-20, KL-A167, STI-A1014, STI-A1015 (IMC-001), BCD-135, FAZ-053, TQB-2450, MDX1105-01, MSB-0010718C, GS-4224, GS-4 416, INCB086550, MAX10181, and multispecific inhibitors FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-013 (PD-1 / LAG-3), FS-118 (LAG-3 / PD-L1), MGD-019(PD-1 / CTLA4), KN-046(PD-1 / CTLA4), MEDI-5752(CTLA4 / PD-1), RO-7121661(PD-1 / TIM-3), XmAb-20717(PD-1 / CTLA4), AK-104(CTLA4 / PD-1),Examples include, but are not limited to, M7824 (PD-L1 / TGFβ-EC domain), CA-170 (PD-L1 / VISTA), CDX-527 (CD27 / PD-L1), LY-3415244 (TIM3 / PDL1), GNS-1480 (epidermal growth factor receptor antagonist; programmed cell death ligand 1 inhibitor), M-7824 (PD L1 / TGFβ bifunctional fusion protein), and INBRX-105 (4-1BB / PDL1).

[0108] Example of PD-1 blocking agent, International Publication No. 2017112730 (Incyte Corp), Same No. 2017087777 (Incyte Corp), Same No. 2017017624, Same No. 2014151634 (BristolMyers Squibb Co), Same as No. 201317322 (BristolMyers Squibb Co), Same as No. 2018119286 (Incyte Corp), Same as No. 2018119266 (Incyte Corp), Same as No. 2018119263 (Incyte Corp), Same as No. 2018119236 (Incyte Corp) Corp), same as No. 2018119221 (Incyte Corp), same as No. 2018118848 (BristolMyers Squibb (Co), same as No. 20161266460 (BristolMyers Squibb Co), same as No. 2017087678 (BristolMyers Squibb Co), same as No. 2016149351 (BristolMyers Squibb Co), same as No. 2015033299 (Aurigene Discovery Technologies Ltd), same as No. 2015179615 (Eisai Co Ltd; Eisai Research Institute), same as No. 2017066227 (BristolMyers Squibb Co), same as No. 2016142886 (Aurigene Discovery Technologies Ltd), same as No. 2016142852 (Aurigene Discovery Technologies Ltd), same as No. 2016142835 (Aurigene Discovery Technologies Ltd; Individual), same as No. 2016142833 (Aurigene Discovery Technologies) Ltd), Same No. 2018085750 (BristolMyers Squibb Co), Same No. 2015033303 (Aurigene Discovery Technologies Ltd), Same No. 2017205464 (Incyte Corp), Same No. 2016019232 (3M Co; Individual; Texas A&M UniversitySystem), No. 2015160641 (BristolMyers Squibb Co), No. 2017079669 (Incyte Corp), No. 2015033301 (Aurigene Discovery Technologies Ltd), No. 2015034820 (BristolMyers Squibb Co), No. 2018073754 (Aurigene Discovery Technologies Ltd), No. 2016077518 (BristolMyers Squibb Co), No. 2016057624 (BristolMyers Squibb Co), No. 2018044783 (Incyte Corp), No. 2016100608 (BristolMyers Squibb Co), No. 2016100285 (BristolMyers Squibb Incyte Corp., No. 2016039749 (BristolMyers Squibb Co.), No. 2015019284 (Cambridge Enterprise Ltd), No. 2016142894 (Aurigene Discovery Technologies Ltd), No. 2015134605 (BristolMyers Squibb Co.), No. 2018051255 (Aurigene Discovery Technologies Ltd), No. 2018051254 (Aurigene Discovery Technologies Ltd), No. 2017222976 (Incyte Corp.), No. 2017070089 (Incyte Corp.), No. 2018044963 (BristolMyers Squibb Co.), No. 2013144704 (Aurigene Discovery Technologies Ltd), No. 2018013789 (Incyte Incyte Corp; MerckExamples of compounds listed include, but are not limited to, those described in Sharp & Dohme Corp., Incyte Corp. (No. 2017192961), Incyte Corp. (No. 2017106634), Aurigene Discovery Technologies Ltd. (No. 2013132317), Aurigene Discovery Technologies Ltd. (No. 2012168944), Aurigene Discovery Technologies Ltd. (No. 2015036927), Aurigene Discovery Technologies Ltd. (No. 2015044900), and Arising International (No. 2018026971).

[0109] PD-1 / PD-L1 inhibitors can be administered in any preferred amount known to those skilled in the art. In some embodiments, the compound of formula I is administered to a subject in amounts of 0.1 to 1000 mg. Typical amounts of PD-1 / PD-L1 inhibitor administered to a subject include, but are not limited to, 0.1 to 500 mg, 1 to 100 mg, 1 to 50 mg, or 10 to 50 mg. Other amounts of PD-1 / PD-L1 inhibitor administered to a subject include, but are not limited to, about 1 mg, or 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or about 100 mg.

[0110] In some embodiments, the methods described herein further include administering an anti-TIGIT antibody such as BMS-986207, RG-6058, or AGEN-1307.

[0111] In some embodiments, the methods described herein further include administering a BTK (Bruton's tyrosine kinase) inhibitor. Examples of such BTK inhibitors are compounds disclosed in U.S. Patent No. 7,405,295. Additional examples of BTK inhibitors include, but are not limited to, (S)-6-amino-9-(1-(buta-2-inoyl)pyrrolidine-3-yl)-7-(4-phenoxyphenyl)-7H-purine-8(9H)-one, acalabrutinib (ACP-196), BGB-3111, HM71224, ibrutinib, M-2951, tirabrutinib (ONO-4059), PRN-1008, spebralutinib (CC-292), and TAK-020. In some embodiments, the BTK inhibitor is selected from acalabrutinib, tirabrutinib, zanubrutinib, and PCI-32765.

[0112] In some embodiments, the anticancer agent is a chemotherapy agent.

[0113] In some embodiments, the anticancer agent is selected from the drugs of Example 3 listed in Table 21. In some embodiments, the chemotherapeutic agent is docetaxel. In some embodiments, the chemotherapeutic agent is gemcitabine. In some embodiments, the chemotherapeutic agent is paclitaxel.

[0114] In some embodiments, the anticancer agent is selected from doxorubicin (DOX), epirubicin, morpholinodoxorubicin (morpholino-DOX), cyanomorpholino-doxorubicin (cyanomorpholino-DOX), 2-pyrrolino-doxorubicin (2-PDOX), CPT, 10-hydroxycamptothecin, SN-38, topotecan, rootthecan, 9-aminocamptothecin, 9-nitrocamptothecin, taxane, geldanmycin, ansamycin, and epotilon.

[0115] In some embodiments, the methods disclosed herein further include administering an antibody-drug conjugate. In some embodiments, the antibody-drug conjugate comprises an anti-Trop-2 antibody. In some embodiments, the antibody-drug conjugate is sacituzumab govitecan. In some embodiments, the antibody-drug conjugate is datopotamab deruxtecan.

[0116] In some embodiments, when the agents of this disclosure are combined with one or more additional therapeutic agents described herein, the components of the composition are administered simultaneously or in a sequential regimen. If administered sequentially, the combination may be administered in two or more doses. In some embodiments, when the agents of this disclosure are combined with one or more additional therapeutic agents described herein, the components of the composition are administered simultaneously or in a sequential regimen. If administered sequentially, the combination may be administered in two or more doses. In some embodiments, when the agents of this disclosure are combined with one or more additional therapeutic agents described herein, the components of the composition are administered simultaneously or in a sequential regimen. If administered sequentially, the combination may be administered in two or more doses.

[0117] Co-administration of the agents disclosed herein with one or more additional therapeutic agents generally refers to co-administration or sequential administration of the agents disclosed herein with one or more additional therapeutic agents such that a therapeutically effective amount of each agent is present in the patient's body.

[0118] Co-administration involves administering a unit dose of the drug disclosed herein before or after the administration of a unit dose of one or more additional therapeutic agents. The drug disclosed herein may be administered within seconds, minutes, or hours of the administration of one or more additional therapeutic agents. For example, in some embodiments, a unit dose of the drug disclosed herein is administered first, followed by a unit dose of one or more additional therapeutic agents within seconds or minutes. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by a unit dose of the drug disclosed herein within seconds or minutes. In some embodiments, a unit dose of the drug disclosed herein is administered first, followed by a unit dose of one or more additional therapeutic agents several hours later (e.g., 1 to 12 hours). In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by a unit dose of the drug disclosed herein several hours later (e.g., 1 to 12 hours).

[0119] In some embodiments, the Disclosure provides a method for treating or preventing cancer. In certain embodiments, the Disclosure provides a method for treating or preventing cancer comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to an individual. In some embodiments, the cancer is a hematological cancer. In some embodiments, the cancer is multiple myeloma. In some embodiments, the cancer is selected from the group consisting of breast cancer, colorectal cancer, skin cancer, melanoma, ovarian cancer, kidney cancer, small cell lung cancer, non-small cell lung cancer, lymphoma, and leukemia. [Examples]

[0120] Example 1: In vitro synergistic effect of MCL-1 inhibitor with SN-38 in TNBC and NSCLC cell lines To test the potential for co-administration between compound A and SN-38 (a topoisomerase inhibitor), an in vitro study was performed in a panel of triple-negative breast cancer (TNBC, n=3) and non-small cell lung cancer (NSCLC, n=2) cell lines using the Bliss independence model for synergistic effects. Cells were exposed to dose titration matrices with each compound alone and in combination for 72 hours, and cell viability was then determined using the Cell Titer Glo reagent. A strong Bliss synergy score (>100) was observed in all cell lines tested. Materials and methods Cell culture and reagents

[0121] HCC70 (ATCC® CRL-2315), HCC1806 (ATCC® CRL-2335), HCC1187 (ATCC® CRL-2322), NCI-H522 (ATCC® CRL-5810), and H820 (ATCC® HTB-181) cell lines were thawed from liquid nitrogen storage and maintained in RPMI-1640 (Gibco-12633) + 10% HI-FBI (Gibco-16140) + Pen / Strep (100×Gibco-15140) according to ATCC guidelines. The cells were passaged using 0.25% trypsin / EDTA (1×GIBCO-25200) according to ATCC guidelines.

[0122] SN-38 and compound A stock (provided by Gilead Sample Bank) were directly dispensed into treatment wells using a D300e Digital Dispenser (seller) with DMSO (Sigma-D2438) up to 0.1% v / v as a vehicle control.

[0123] Survival was assessed using Cell Titer Glo® (Promega#G9241) according to the manufacturer's microwell plate protocol, and luminescence was read using a Biotek Synergy Neo2 plate reader. Cell viability combination assay

[0124] For the synergistic action matrix assay, cell lines were seeded at 5,000 cells per well in a clear-bottom white 96-well plate (Corning #3909) in 100 μL of the recommended cell culture medium. The treatment map consisted of a single-agent dose response for compound A (7 three-fold dilutions + untreated control) or SN-38 (9 three-fold dilutions + untreated control) and a checkerboard matrix of 63 different combinations. The concentration ranges were selected based on the relative sensitivity of each cell line to the compounds. Five plates were used for each combination to generate sufficient replicates to calculate the synergistic score with a 95% confidence interval (95% CI).

[0125] The HP D300 dispenser was used to apply the compounds and DMSO vehicle to the cells, directly dispensing them into the medium according to the checkerboard matrix, incubating at 37 °C / 5% CO2 / 100% relative humidity for 72 hours, and then measuring viability by Cell Titer Glo. Data analysis

[0126] Combined viability data were evaluated for synergy using an Excel template described by Prichard and Shipman {Prichard 1990}. Specifically, the single-component dose curves for SN-38 and compound A were normalized against the viability (%) on each plate, averaged over five technical replicate experiments, and the theoretical additive kill of the combination was calculated according to the Bliss independence principle. The calculated values were compared with the experimental results generated in the 63-concentration checkerboard. Synergy or antagonism scores were created according to whether the observed growth inhibition was greater or less than the calculated values, respectively.

[0127] For example, if two compounds (B) and (C) at a given concentration each produced 60% inhibition, their theoretical additive inhibition would be 84% according to the following Bliss independence equation. 60% B +60% C * (100% - 60% B ) = 84% B+C If the experimental result is greater than the calculated value (e.g., 90% inhibition), the difference [6%] is added to the synergistic effect score. If the result is less than the calculated value (e.g., 78% inhibition), the difference [6%] is added to the antagonistic effect score.

[0128] These differences are summed up across the entire checkerboard (63 wells) to obtain the cumulative synergistic and antagonistic scores in μM. 2 The scores were given in percentages to reflect the 2D surface of the dose-response. 95% confidence interval adjustments were applied to the synergistic and antagonistic effect scores, and each sum was compared to the scale based on the original method: scores above 50 were considered moderate synergy, and scores above 100 were considered strong synergy, indicating a high probability of in vivo co-administrative efficacy {Prichard 1990}.

[0129] The data from the combined assays are presented in three formats. Synergy scores in 95% confidence intervals were averaged from n=2 assays. Exemplary tabular and graphical percentage inhibition matrices for each cell line. Exemplary tabular and graphical synergy matrices in 95% confidence intervals for each cell line.

[0130] To test the potential for co-administration between compound A and SN-38 (a topoisomerase inhibitor), an in vitro study was performed in a panel of TNBC (n=3) and NSCLC (n=2) cell lines using the Bliss independence model for synergistic effects. Cells were exposed to dose titration matrices with each compound alone and in combination for 72 hours, and cell viability was then determined using the Cell Titer Glo reagent. A strong Bliss synergy score (>100) was observed in all cell lines tested. [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10] [Table 11] [Table 12] * The SN-38 dose-response shifted at a peak concentration of 1.0 μM, capturing a large potential range of synergistic activity. Example 2: In vitro synergistic effect of paclitaxel and MCL-1 inhibitor in TNBC cells Materials and methods Cell culture and reagents

[0131] HCC70 (ATCC® CRL-2315) and HCC1806 (ATCC® CRL-2335) were thawed from liquid nitrogen storage and maintained in RPMI-1640 (Gibco-12633) + 10% HI-FBI (Gibco-16140) + Pen / Strep (100 × Gibco-15140) according to ATCC guidelines. MDA-MB-468 (ATCC® HTB-132) was thawed and maintained in DMEM (Gibco-11995) + 10% HI-FBS + Pen / Strep. Cells were passaged using 0.25% trypsin / EDTA (1 × GIBCO-25200) according to ATCC guidelines.

[0132] Paclitaxel and compound A stock (provided by Gilead Sample Bank) were dispensed directly into the treatment wells using a D300e Digital Dispenser (seller) with DMSO (Sigma-D2438) up to 0.1% v / v as a vehicle control.

[0133] Survival was assessed using Cell Titer Glo® (Promega#G9241) according to the manufacturer's microwell plate protocol, and luminescence was read using a Synergy Neo2 plate reader.

[0134] Cell lysates for MSD assays were prepared using 1× lysis buffer (10× cell signaling CST-9803), 100× protease inhibitor, phosphatase inhibitor I, phosphatase inhibitor II (Meso Scale Discovery Inhibitor Pack R70AA-1), and PMSF (SIGMA catalog number 7626).

[0135] The MCL-BAK and MCL1-BIM dimer assays, as well as the total MCL1 assay, were developed by MSD Custom Assay Services and performed using the MSD U-PLEX Development Pack (K15227N) and the revised protocol "2018 Mar rev 2". GAPDH was determined by MSD using the standard assay K151PWD. All plates were read using an MSD SECTOR Imager 2400 with an MSD Read Buffer T (R92TC).

[0136] Protein Simple Reagents: EZ Standard Pack 1 (PS-ST01EZ: Biotinylated Ladder, FL Standard and DTT), Peroxide (044-379), Luminal-S (043-311), Antibody Dilution Buffer (042-203), Streptavidin HRP (042-414), Secondary Antibodies: Goat Anti-Rabbit (042-206) and Goat Anti-Mouse (042-205), Separation Matrix (042-512), Stacking Matrix (042-513), 10X Sample Buffer (042-195), Wash Buffer (042-520), Upper Electrophoresis Buffer (043-163), Lower Electrophoresis Buffer (043-162), 384-Well Plate (040-663), Size Capillary (55700), Protein Simple Instruments Peggy Sue (trademark) and Sally Sue(trademark). Primary antibodies: MCL1 (CST-94296), FBXW7 (Abcam 109617 and Abcam 171961). Cell viability combination assay

[0137] For the synergistic matrix assay, TNBC cell lines were seeded at 10,000 cells per well in 100 μL of recommended cell culture medium in a clear-bottomed white 96-well plate (Corning #3909). After incubating the plates at 37°C and 100% RH for 20 hours, they were exposed to the compounds. The treatment maps consisted of monotherapy dose-response data of checkerboard matrices with either compound A (seven 3-fold dilutions of 3 μM to 4 nM + untreated control) or paclitaxel (nine 3-fold dilutions of 3 μM to 0.5 nM + untreated control) and 63 different combinations. Five plates were used for each combination to generate enough replicates to calculate the synergistic score in 95% confidence intervals (95% CI).

[0138] Paclitaxel and DMSO vehicles were first applied to cells using an HP D300 dispenser and ali-coated directly into the medium according to a checkerboard matrix. Paclitaxel was incubated for 4 hours, then washed off by removing the medium, washed with 2 × 200 μL of preheated complete medium, and finally replaced with 100 μL of preheated complete medium. The cells were then exposed to compound A using the same checkerboard matrix with a D300 dispenser and incubated for 48 hours before measuring viability with Cell Titer Glo. MSD assay

[0139] For the MSD assay, TNBC cell lines were seeded at 25,000 cells per well in a clear-bottomed white 96-well plate (Corning #3909) in the recommended cell culture medium. After incubating the plate at 37°C and 100% RH for 20 hours, it was exposed to the compounds. Paclitaxel and DMSO vehicle were first applied to the cells using an HP D300 dispenser and ali-coated directly into the medium. Paclitaxel was incubated for 4 hours, then washed off by removing the medium, washed with 2 × 150 μL of preheated complete medium, and finally replaced with 100 μL of preheated complete medium. After a further 20 hours, the samples were collected by aspirating and removing the supernatant, and 125 μL of 1 × lysis buffer was added to each well. The plate was briefly placed on ice and then transferred to a rocking platform at 4°C for 20 minutes. The plate was placed on dry ice and rapidly frozen for 10 minutes, then stored at -80°C until testing.

[0140] MCL1, MCL1-BAK, and MCL1-BIM dimer assays were performed using materials and protocols provided by MSD Custom Assay Services, based on their U-Plex technology. First, plates were prepared using the standard U-PLEX capture antibody coating protocol and then washed three times with 150 μL of MSD wash buffer. 25 μL of sample or standard was added directly to the plate, the plate was sealed, and incubated at room temperature for 1 hour with shaking. The plate was washed three times with 150 μL of wash buffer per well, 50 μL of antibody detection solution was added to each well of the MSD plate, the plate was sealed, and incubated at room temperature for 1 hour with shaking. The plate was washed again three times with 150 μL of wash buffer per well. 150 μL of 2× read buffer was added to each well, and the plate was read with an MSD SECTOR Imager 2400.

[0141] The GAPDH assay kit (MSD) was performed according to the manufacturer's protocol using 25 μL of lysate per sample added directly to the plate. The plate was sealed and incubated at room temperature for 1 hour with shaking, then washed three times with 150 μL of wash buffer per well. 25 μL of antibody detection solution was added to each well, the plate was sealed and incubated at room temperature for 1 hour with shaking, then washed three times with 150 μL of wash buffer per well. 150 μL of 2× read buffer was then added to each well, and the plate was measured for electrochemiluminescence (ECL) using an MSD SECTOR Imager 2400. Simple Western Protein

[0142] A simple Western immunoassay is performed using a capillary. Samples and reagents are loaded onto an assay plate and placed in a Protein Simple Instrument. Cell lysates are automatically loaded into the capillary and separated by size as they move through the stacking and separation matrix. The separated proteins are then immobilized on the capillary wall via a proprietary photoactivated capture chemistry. Target proteins are identified using a primary antibody and immunoprobed using an HRP-conjugated secondary antibody and a chemiluminescent substrate. The resulting chemiluminescent signals are detected and quantified.

[0143] FBXW7 expression was measured in cell lines after 4 hours of administration of 1 μM paclitaxel, followed by rinsing and overnight incubation using Simple Western. Lysates were prepared and diluted to 0.5 μg / ml with 1× lysis buffer. The Simple Western platform was run on a 384-well plate.

[0144] The marker, internal ladder, and DTT are supplied by Simple Western in lyophilized form. Resuspend the reagents as described in the protocol. Add 20 μL of water to the marker. Add 40 μL of water to the DTT, mix with 20 μL of 10X sample buffer and 20 μL of DTT, and call this Z buffer. Load the marker into 1A. Add 5 μL of lysate to a 1.7 ml Eppendorf tube. Add 1.2 μL of Z reagent to each sample. Heat the samples at 100C for 5 minutes, let them cool, and then centrifuge them in a microcentrifuge for 30 seconds. Load the samples into wells A2-A12. Dilute the primary antibody 1:50 with antibody dilution buffer (6 μL + 294 μL dilution buffer). Load 20 μL of each antibody into lanes 2-A12. There are a maximum of 8 different antibodies in each column. Actin diluted 1:300 was used as a loading control. Furthermore, a secondary antibody against either goat or rabbit, or goat or mouse, is loaded as needed. The plate is rotated at 2.6k RT for 10 minutes, loaded into the instrument, and run overnight. The target protein is identified using the primary antibody and immunoprobed using an HRP-conjugated secondary antibody and a chemiluminescent substrate. The resulting chemiluminescent signal is detected and quantified. Data Analysis About Bliss synergy

[0145] Combination survival data were evaluated for synergistic effects using an Excel template described by Prichard and Shipman (Prichard 1990). Specifically, single-component dose curves for paclitaxel and compound A were normalized to survival percentage (%) on each plate and averaged over five technically replicated experiments to calculate the theoretical additive mortality of the combination according to the principle of Bliss independence. The calculated values ​​were compared with experimental results generated using a 63-concentration checkerboard. Synergistic or antagonistic scores were created depending on whether the observed growth inhibition was greater or less than the calculated value.

[0146] For example, if two compounds (B) and (C) at a given concentration each produce 60% inhibition, their theoretical additive inhibition is 84% ​​according to the following Bliss independence formula. 60% B +60% C * (100%-60% B ) = 84% B+C

[0147] If the experimental result is greater than the calculated value (e.g., 90% inhibition), the difference [6%] is added to the synergistic effect score. If the result is less than the calculated value (e.g., 78% inhibition), the difference [6%] is added to the antagonistic effect score.

[0148] These differences are summed up across the entire checkerboard (63 wells) to obtain the cumulative synergistic and antagonistic scores in μM. 2 The scores were given in percentages to reflect the 2D surface of the dose-response. 95% confidence interval adjustments were applied to the synergistic and antagonistic effect scores, and each sum was compared to the scale based on the original method: scores above 50 were considered moderate synergy, and scores above 100 were considered strong synergy, indicating a high probability of in vivo co-administrative efficacy {Prichard 1990}.

[0149] The data from the combined assays are presented in three formats. Synergy scores in 95% confidence intervals were averaged from n=2 assays. Exemplary tabular and graphical percentage inhibition matrices for each cell line. Exemplary tabular and graphical synergy matrices in 95% confidence intervals for each cell line. MSD assay

[0150] For total MCL1, the ECL signal was recorded and converted to pg / mL via an 8-point standard dose range (0–10,000 pg / mL) using a calibration control developed by MSD, and a 4-parameter curve fitting function was used in MSD WorkBench software. The results for MCL1-BAK and MCL1-BIM dimers were converted to pg / mL using the same process, but the standard concentrations were in the range of 0–50,000 pg / mL. GAPDH results were recorded and reported as ECL and used to normalize both MCL1 and MCL1 dimers within each sample set. For graphical comparisons between analytes of a given cell line, each pg / mL dataset was normalized to 100% relative to the vehicle control, with no protein set to 0%.

[0151] Paclitaxel has been reported to downregulate MCL1 protein levels, partly through an increase in the MCL1 E3-ligase FBXW7, which targets MCL1 for proteasomal degradation {Wertz 2011}. To confirm this observation, HCC70, MDA-MB-468, and HCC1806 TNBC cell lines were treated with clinically appropriate concentrations of paclitaxel (1 μM) for 4 hours (Gianni 1995). After paclitaxel treatment, cells were incubated overnight and protein levels were determined. Comparison of paclitaxel-treated cells with vehicle controls revealed elevated FBXW7 protein levels and decreased MCL1 protein levels (Table 13 and Figure 1). Paclitaxel treatment also resulted in decreased levels of MCL1-BAK and MCL1-BIM dimer proteins (Table 13 and Figure 1). These results were observed across all three TNBC cell lines (n=3 biological replicates).

[0152] The HCC70, MDA-MB-468, and HCC1806 TNBC cell lines were treated with a clinically relevant concentration of paclitaxel (1 μM) for 4 hours (Gianni 1995). Paclitaxel treatment increased the FBXW7 protein level, decreased the MCL1 protein level, and decreased the protein levels of the MCL1-BAK and MCL1-BIM dimers in all three cell lines. HCC70, MDA-MB-468, and HCC1806 were pretreated with increasing doses of paclitaxel (adjusted to C max = 1 μM included) for 4 hours to mimic clinical exposure and then exposed to increasing doses of Compound A for 72 hours, and Bliss synergy (> 100) was observed.

Table 13

[0153] To determine whether the decrease in MCL1 protein level after paclitaxel treatment led to enhanced sensitivity to Compound A, Bliss synergy was used. HCC70, MDA-MB-468, and HCC1806 were pretreated with increasing doses of paclitaxel (adjusted to C max = 1 μM included) for 4 hours to mimic clinical exposure and then exposed to increasing doses of Compound A. Cells were incubated for 72 hours, and viability was determined using the CTG reagent. Bliss synergy was observed across all three TNBC cell lines exposed to the combination of Compound A and paclitaxel in vitro (Table 15). A Bliss synergy score of greater than 100 is considered a strong effect {Prichard 1990}.

Table 14

Table 15

Table 16

Table 17

Table 18

Table 19

Table 20

Table 21-1

Table 21-2

Table 21-3

Table 21-4

Table 21-5

Table 21-6

Table 21-7

Table 21-8

Table 21-9

Table 21-10

Table 21-11

Table 21-12

[0154] The trial will be conducted to characterize the safety and tolerability of compound A and compound A in combination with anticancer therapy in subjects with advanced solid malignancies. Test design

[0155] This is an open-label, multicenter, dose-escalation, and dose-expansion Phase 1a / 1b study to evaluate the safety, tolerability, and PK profile of compound A, record any DLTs (dose-limiting toxicity), and determine the MTD (maximum tolerated dose) and / or RP2D (recommended Phase 2 dose) of compound A as monotherapy and in combination with anticancer therapy in subjects with advanced solid malignancies. The RP2D is the dose level(s) that is tolerable, exposure-effective, and biomarker-active. The study consists of two phases: Phase 1a (dose-expansion) followed by Phase 1b (dose-expansion). • Phase 1a dose escalation: Part A: Dose escalation of compound A as monotherapy • Phase 1b dose expansion: Part B: An optional disease-specific cohort of compound A in combination with anticancer therapy, conducted in parallel with Part A. Part C: Safety introduction and expansion of compound A in combination with anticancer therapy following Parts A and B.

[0156] Each part of the study consists of screening, treatment, and follow-up periods. Screening is performed up to 28 days before the first dose of the study treatment, during which time the eligibility and baseline characteristics of the subjects are determined. Part A: Phase 1a dose escalation of compound A as monotherapy.

[0157] Patients with advanced solid tumors that have failed or are intolerant to standard therapy, or for which no standard therapy exists, are sequentially enrolled to receive compound A as monotherapy at progressively increasing dose levels.

[0158] Dose escalation is carried out using a dose escalation design based on the 3+3 rule.

[0159] Compound A is administered orally on days 1, 2, 8, 9, 15, and 16 of each 21-day cycle for up to 105 weeks.

[0160] Up to six cohorts (i.e., six dose levels) with 3 to 6 subjects each will receive compound A at escalating dose levels as monotherapy. The planned starting dose of compound A is 5 mg, with target doses of 15 mg and 50 mg for the following two cohorts. Subsequent dose levels following the starting dose will be determined based on all available clinical data, including safety, tolerability, and pharmacokinetics (PK) from previous cohorts, and approved by the Safety Review Team (SRT), potentially up to 300 mg. Dose level increases will be semi-logarithmic or less in each subsequent dose escalation.

[0161] The safety and tolerability of each dose level will be assessed by SRT after all subjects in the cohort have been followed for at least 21 days after the first dose of compound A, or after subjects have had a DLT during the first 21 days of investigational drug administration.

[0162] Each dose in the initial block consists of three subjects. If no subjects experience a DLT (Drug Level T) during the first 21 days of investigational drug administration, a dose escalation is performed. If one subject in the initial cohort of three subjects experiences a DLT during the first 21 days of investigational drug administration, an additional three subjects are enrolled at the same dose level. If no DLT is observed in the additional three subjects, a dose escalation is performed. If two or more subjects experience a DLT within the first 21 days, a dose reduction to a lower dose is performed. The MTD (Mean Time Tolerance) is the highest dose level with a DLT incidence rate of less than 33% during the first 21 days of investigational drug administration.

[0163] The decision rule to apply is a 21-day treatment regimen consistent with any given cohort.

[0164] Throughout the trial, subjects with malignant tumors for which biopsy is available may undergo optional tumor biopsies. These subjects must consent and provide separate, specific written consent. Dosage escalation criteria

[0165] For any given cohort, the sponsor may choose to withhold medication, select an intermediate dose, or discontinue study enrollment at any time, based on a review of preliminary safety and available PK and / or pharmacodynamic data.

[0166] Based on a review of relevant safety and available PK and / or pharmacodynamic data from the SRT, dose escalation to higher dose cohorts should only be performed in the absence of a DLT and / or in the meeting of any pre-specified discontinuation criteria. Dose escalation to subsequent cohorts on a scale larger than half-log requires affirmation by at least two-thirds of the SRTs.

[0167] Dose-limiting toxicity is defined as the following compound A-related events that occur within the first 21 days (after the first administration of compound A). • Grade 4 hematological toxicity lasting more than 21 days. All compound A-related grade 3 non-hematological toxicity lasting more than 7 days, and all compound A-related grade 4 non-hematological toxicity regardless of duration, are considered DLTs. Part B: An optional disease-specific cohort of compound A in combination with anticancer therapy, conducted in parallel with Part A.

[0168] During monotherapy dose escalation in Part A, and prior to formal dose expansion of sponsor-nominated and supported disease-specific cohorts featuring combination therapy with compound A in Part C, the sponsor may choose to nominate and support one or more of the following cohorts aligned with those in Part C for any previously evaluated dose of combination therapy with compound A in Part A that is deemed safe and tolerable by the SRT. • Cohort B1: Metastatic NSCLC (Compound A + Docetaxel) • Cohort B2: Metastatic NSCLC (Compound A + sacituzumab govitecan) • Cohort B3: Metastatic TNBC (Compound A + Docetaxel) • Cohort B4: Metastatic TNBC (compound A + sacituzumab govitecan) • Cohort B5: mSTS with nonspecific histology (compound A + docetaxel and gemcitabine)

[0169] Each additional cohort consists of a single such population with a specific combination. Part C: Safety induction and dose expansion of compound A in combination with other anticancer therapies

[0170] This is an open-label Phase 1b trial using compound A in combination with one or more other anticancer therapies from the following five disease-specific cohorts nominated and supported by the sponsor after the completion of Parts A and B. • Cohort C1: Metastatic NSCLC (Compound A + Docetaxel) • Cohort C2: Metastatic NSCLC (Compound A + sacituzumab govitecan) • Cohort C3: Metastatic TNBC (compound A + docetaxel) • Cohort C4: Metastatic TNBC (compound A + sacituzumab govitecan) • Cohort C5: mSTS with nonspecific histology (compound A + docetaxel and gemcitabine)

[0171] RP2D is the dose(s) level(s) that has acceptable tolerability, exposure, and biomarker activity.

[0172] Based on the overall clinical, safety, pharmacokinetic, and pharmacodynamic data, the SRT recommends the initial dose of compound A for use in combination for each cohort. To ensure that the combination therapy is safe and tolerable in each target population, at least three subjects and a safety induction group of no more than six subjects will be enrolled.

[0173] Safety induction will employ the same 3+3 design and dose escalation rules as Part A, and will use the same DLT criteria and DLT evaluation window as Part A to determine the MTD and / or RP2D. A minimum of six subjects must be treated at a certain dose level before this dose level can be increased. If a related disease-specific cohort from Part B is investigated in the RP2D, those subjects may be counted and considered for the safety induction group requirements.

[0174] The expansion will include approximately 30 subjects, fewer than any disease-specific relatives treated with the same regimen investigated under Part B and in any safety introduction. For each disease-specific cohort (B1+C1, B2+C2, B3+C3, B4+C4, B5+C5), a minimum of 20 subjects in RP2D will be enrolled, including any subjects from Part B and / or safety introduction. Cohort C1: Compound A in combination with docetaxel in metastatic NSCLC after single-line therapy for metastatic disease

[0175] Cohort C1 evaluates safety and tolerability in subjects with metastatic NSCLC following single-line therapy for metastatic disease, and defines the DLT(s) and MTD and / or RP2D of compound A in combination with docetaxel.

[0176] Compound A is administered on days 1, 2, 8, 9, 15, and 16 of the 21-day cycle.

[0177] Docetaxel is administered when the target neutrophil count is acceptable on the day of administration, specifically when it is ≥1500 cells / mm³. 3 Under these conditions, 75 mg / m² is administered as an IV infusion over one hour on day 1 of every 21-day cycle. 2 The medication is administered based on body surface area (BSA).

[0178] Treatment will continue for up to 105 weeks unless one or more discontinuation criteria are met. Cohort C2: Compound A in combination with sacituzumab govitecan in metastatic NSCLC after single-line therapy for metastatic disease

[0179] Cohort C2 evaluates safety and tolerability in subjects with metastatic NSCLC after single-line therapy for metastatic disease and defines the DLT(s) and MTD and / or RP2D of compound A in combination with sacituzumab govitecan.

[0180] Compound A is administered on days 1, 2, 8, 9, 15, and 16 of the 21-day cycle.

[0181] Sacituzumab govitecan is administered when the target neutrophil count is acceptable on the day of administration, specifically when it is ≥1500 cells / mm³ on day 1 of any cycle. 3 Alternatively, on day 8 of any cycle, the absolute neutrophil count (ANC) is ≥ 1000 cells / mm³. 3 Under the condition that the drug is administered IV at a dose of 10 mg / kg once a week on days 1 and 8 of each 21-day cycle. The first infusion should be administered over 3 hours, and the subject should be observed for signs or symptoms of infusion-related reactions both during and for at least 30 minutes after the infusion. Subsequent infusions should be administered over 1-2 hours, if the previous infusion was tolerated, and the subject should be observed both during and for at least 30 minutes after the infusion.

[0182] Treatment will continue for up to 105 weeks unless one or more discontinuation criteria are met. Cohort C3: Compound A combined with docetaxel in metastatic TNBC after single-line therapy for metastatic disease.

[0183] Cohort C3 evaluates safety and tolerability in subjects with metastatic TNBC after single-line therapy for metastatic disease, and defines the DLT(s) and MTD and / or RP2D of compound A in combination with docetaxel.

[0184] Compound A is administered on days 1, 2, 8, 9, 15, and 16 of the 21-day cycle.

[0185] Docetaxel is administered when the target neutrophil count is acceptable on the day of administration, specifically when it is ≥1500 cells / mm³. 3 Under these conditions, 75 mg / m² is administered as an IV infusion over one hour on day 1 of every 21-day cycle. 2 It is administered with BSA.

[0186] Treatment will continue for up to 105 weeks unless one or more discontinuation criteria are met. Cohort C4: Combination of sacituzumab govitecan and compound A in metastatic TNBC after single-line therapy for metastatic disease

[0187] Cohort C4 evaluates safety and tolerability in subjects with metastatic TNBC after single-line therapy for metastatic disease and defines the DLT(s) and MTD and / or RP2D of compound A in combination with sacituzumab govitecan.

[0188] Compound A is administered on days 1, 2, 8, 9, 15, and 16 of the 21-day cycle.

[0189] Sacituzumab govitecan is administered when the target neutrophil count is acceptable on the day of administration, specifically when it is ≥1500 cells / mm³ on day 1 of any cycle. 3 Alternatively, on day 8 of any cycle, ANC ≥ 1000 cells / mm³ 3 Under the condition that the drug is administered IV at a dose of 10 mg / kg once a week on days 1 and 8 of each 21-day cycle. The first infusion should be administered over 3 hours, and the subject should be observed for signs or symptoms of infusion-related reactions both during and for at least 30 minutes after the infusion. Subsequent infusions should be administered over 1-2 hours, if the previous infusion was tolerated, and the subject should be observed both during and for at least 30 minutes after the infusion.

[0190] Treatment will continue for up to 105 weeks unless one or more discontinuation criteria are met. Cohort C5: Metastatic soft tissue sarcomas with nonspecific histology that have not been previously treated for metastatic disease.

[0191] Cohort C5 evaluates safety and tolerability and defines the DLT(s) and MTD and / or RP2D of compound A in combination with gemcitabine and docetaxel in subjects with previously untreated soft tissue sarcoma.

[0192] Compound A is administered on days 1, 2, 8, 9, 15, and 16 of the 21-day cycle.

[0193] Gemcitabine is administered as an IV infusion of 900 mg / m2 BSA at a fixed dose rate over 90 minutes on days 1 and 8, while docetaxel is administered as 100 mg / m2 BSA IV over 60 minutes on day 8 of every 21-day cycle.

[0194] Treatment will continue for up to 105 weeks unless one or more discontinuation criteria are met. Duration of treatment

[0195] Research drug compound A may be administered for up to 105 weeks, or until the first occurrence of disease progression, unacceptable toxicity, substantial non-compliance with the research procedure or research drug, study interruption, withdrawal from the study, or any other reason. References Ashkenazi A, Fairbrother WJ, Leverson JD, Souers AJ. From basic apoptosis discoveries to advanced selective BCL-2 family inhibitors. Nat Rev Drug Discov 2017;16(4):273-84. Gianni L,Kearns CM,Giani A,Capri G,Vigano L,Lacatelli A,et al.Nonlinear pharmacokinetics and metabolism of paclitaxel and its pharmacokinetic / pharmacodynamic relationships in humans.J Clin Oncol 1995;13(1):180-90. Juin P,Geneste O,Gautier F,Depil S,Campone M.Decoding and unlocking the BCL-2 dependency of cancer cells.Nat Rev Cancer 2013;13(7):455-65. Prichard MN,Shipman C,Jr.A three-dimensional model to analyze drug-drug interactions.Antiviral Res 1990;14(4-5):181-205. Ruefli-Brasse A,Reed JC.Therapeutics targeting Bcl-2 in hematological malignancies.Biochem J 2017;474(21):3643-57. Wertz IE,Kusam S,Lam C,Okamoto T,Sandoval W,Anderson DJ,et al.Sensitivity to antitubulin chemotherapeutics is regulated by MCL1 and FBW7.Nature 2011;471(7336):110-4. Youle RJ,Strasser A.The BCL-2 protein family:opposing activities that mediate cell death.Nat Rev Mol Cell Biol 2008;9(1):47-59.

Claims

1. It is a combination of treatments for cancer. This includes administering a therapeutically effective dose of an anticancer drug and a therapeutically effective dose of an MCL-1 inhibitor. The aforementioned combination is characterized by being administered to human patients who require it. The aforementioned MCL-1 inhibitor is compound A: 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, and Here, the anticancer agent is a topoisomerase inhibitor, and here, the topoisomerase inhibitor is SN-38, and here, the cancer is selected from breast cancer and lung cancer. A combination of items.

2. The combination according to claim 1, wherein the cancer is selected from TNBC and NSCLC.

3. The combination according to claim 1, wherein the cancer is metastatic.

4. The combination according to claim 1, wherein the cancer is metastatic non-squamous non-small cell lung cancer (mNSCLC).

5. The combination according to claim 1, wherein the cancer is metastatic triple-negative breast cancer (mTNBC).

6. The combination according to claim 1, wherein the cancer is a metastatic soft tissue sarcoma having nonspecific histology.

7. The combination according to claim 1, wherein the human patient has received at least one other therapy prior to treatment with the combination.

8. The combination according to claim 1, wherein the human patient has failed to receive therapy with an anti-PD1 agent or an anti-PDL1 agent prior to treatment with the combination.

9. The combination according to claim 1, wherein the compound A or a pharmaceutically acceptable salt thereof and the anticancer agent are administered simultaneously or separately.

10. The combination according to claim 1, wherein compound A or a pharmaceutically acceptable salt thereof is administered orally.

11. The combination according to claim 1, wherein the amount of compound A or a pharmaceutically acceptable salt thereof is administered in doses of about 5 mg / kg, about 15 mg / kg, or about 50 mg / kg.

12. The combination according to claim 1, wherein compound A or a pharmaceutically acceptable salt thereof is administered at a dose of about 5 mg / kg.

13. The combination according to claim 1, wherein compound A or a pharmaceutically acceptable salt thereof is administered in a 21-day cycle consisting of two days of administration followed by five days of rest.

14. The combination according to claim 1, wherein compound A or a pharmaceutically acceptable salt thereof is administered on days 1, 2, 8, 9, 15 and 16 of each 21-day cycle for up to 105 weeks.

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