EA046626B1 - METHOD FOR IDENTIFYING SUBJECTS HAVING A RESPONSE TO AGENTS THAT DESTROY SMARCA2/4 - Google Patents

Description

Related Application

This application claims priority to Indian Provisional Patent Application No. 201941036639 filed on September 12, 2019; the contents of which are incorporated herein by reference in their entirety.

Field of technology

The present invention provides methods for treating prostate cancer in a subject who has responded to treatment with at least one SMARCA2/4 disrupting agent.

State of the art

Prostate cancer (PrCa), the most common cancer in men, is the second leading cause of cancer death in men in the United States and the fifth leading cause of cancer death in men worldwide. The present invention is based on the identification of biomarkers to predict the susceptibility of prostate cancer cells and thus the susceptibility of prostate cancer patients to therapy with agents that disrupt SMARCA2/4, the catalytic subunits of the SWI/SNF chromatin remodeling complex. In particular, the invention is based on the new discovery that disruption of SMARCA2/4 function blocks the growth of prostate cancer cells under one or more conditions, including: a) the presence of the androgen receptor (AR), b) a mutation in the tumor suppressor gene PTEN, and c) the presence TMPRSS2-ERG gene fusions. The invention represents a significant advance over existing knowledge in the art, since at the time of filing there was no systematic approach to identify these biomarkers to predict cell susceptibility to agents that destroy SMARCA2/4.

The androgen receptor (AR) is a steroid receptor transcription factor for testosterone and dihydrotestosterone. AR plays a key role in PrCa, particularly in castration-resistant prostate cancer (CRPC). Androgen deprivation therapy can suppress prostate cancer that has not previously been treated with hormones, but prostate cancer alters the AR and adapts to survive castration levels of androgens. These mechanisms include AR point mutations, increased AR expression, alterations in androgen biosynthesis, AR splice variants with constitutive non-ligand activity, and alterations in androgen cofactors. Studies of AR in CRPC have shown that AR retains activity in CRPC and remains a potential target for the treatment of CRPC. Enzalutamide is a second-generation antiandrogen effective in patients with CRPC before and after taxane-based chemotherapy. However, CRPC remains incurable and can become drug resistant. Understanding the mechanisms of this resistance may allow the development of new generation therapies for CRPC (Tan et al. Acta Pharmacol Sin. 2015 Jan; 36(1): 3-23).

Studies have shown that the SWI/SNF complex regulates androgen receptor-mediated gene expression and proliferation of prostate cancer cell lines (Jin et al., Biochem Biophys Res Commun. 2018, Oct 28; 505(2): 618-623). However, data on a therapeutic agent targeting components of the SWI/SNF complex are not available.

Genetic and epigenetic changes, including but not limited to phosphatase and tensin homolog (PTEN) deletion, TMPRSS2-ERG translocation, SPOP mutation, and Myc amplification, contribute to the progression of PrCa. Loss of PTEN and hyperactivation of PI3K/AKT signaling are implicated as determinants of the development of tumors pathologically associated with PrCa. Approximately 30% of primary tumors and up to 70% of metastatic cancers are characterized by loss of heterozygosity in the PTEN gene locus. Similarly, genetically engineered mice (GEMs) have shown a key role for PTEN signaling in PrCa. Prostate-specific deletion of Pten (PtenPC-/-) leads to the development of prostate adenocarcinoma after a long latent period. In addition, loss of Pten is functionally correlated with other signal transduction changes, such as deletion of Tr53 or Nkx3.1 and increased expression of ERG or KrasG12D, causing dramatic disease in mice. Together, these results highlight the functional importance of PTEN in prostate tumorigenesis. However, targeting the PTEN or PI3K/AKT pathway with pharmacological agents remains a major barrier to disease treatment.

A publication (Ding et al., J Clin Invest. 2019;129(2):759-773) showed that increased SMARCA4 expression in tumors with low PTEN expression was associated with worse clinical outcome. Genetic engineered mouse (GEM) and organoid studies confirmed that deletion of PTEN increased the susceptibility of cells to SMARCA4 depletion. Mechanistically, loss of PTEN stabilized SMARCA4 protein through inhibition of the AKT-GSK3b-FBXW7 axis. Overexpression of SMARCA4 in PTEN-deficient PrCa cells resulted in chromatin remodeling in configurations that drive the tumorigenesis-promoting transcriptome, causing further cell dependence on SMARCA4. In addition, the authors showed in preclinical models that a BRG1 antagonist selectively suppressed the progression of PTEN-deficient prostate tumors. However, the present inventors, using the reported SMARCA4 bromodomain inhibitors, were unable to detect susceptibility in cell lines

- 1 046626 PTEN-deficient prostate cancer, which would be consistent with the lack of antiproliferative activity when using SMARCA2/4 inhibitors by different groups.

Approximately half of all prostate cancers involve translocation of the ERG transcription factor and the androgen-regulated gene TMPRSS2. As a result, ERG is expressed in large quantities in the prostate gland, in which it is not normally expressed. Several mouse models have demonstrated its role in prostate cancer development, however, the precise action of TMPRSS2-ERG in tumorigenesis remains unknown, making it difficult to target therapeutics on its function. Additionally, historically, small molecule pharmacological targeting of transcription factors has been fraught with difficulty.

A recent study (Sandoval et al., 2018, Molecular Cell 71, 1-13) showed that binding of the ERG transcription factor to the SWI/SNF complex promotes genome-wide retargeting and gene regulation. They also showed that the ATPase activity of the SWI/SNF complex (present in SMARCA2 and SMARCA4) is required for ERG-mediated target gene regulation in cell line and organoid models, thereby demonstrating the mutual dependence of the ERG and BAF complexes in prostate cancer. However, there are no reports describing selective disruption of SMARCA2/4 as a therapeutic approach for targeted treatment of prostate cancer.

The data described above highlight the role of AR, PTEN deletion, and the presence of the TMPRSS2-ERG fusion in prostate cancer, and the requirement of a functional SWI/SNF complex, including functional SMARCA2/4, for these changes supporting prostate cancer progression. However, there are no reports indicating that disruption of SMARCA2/4 may result in antiproliferative activity through a synthetic lethality-determining relationship.

There are many reports in the literature that suggest that a patient's genetic profile may determine a patient's susceptibility to any particular therapeutic treatment. Given the fact that a variety of therapies are available to individuals suffering from cancer, identifying a patient's genetic factors that influence response to a particular drug can be used to offer that patient a personalized treatment regimen. These personalized treatment regimens achieve maximum therapeutic benefit for the patient while minimizing associated side effects that may be associated with alternative and less effective treatment regimens. Thus, there is a need to identify factors that can be used to predict a patient's potential response to therapeutic treatment. In particular, it is important to identify these prognostic factors in the field of cancer biology and to exploit discoveries related to key synthetic lethality nodes in prostate cancer for therapeutic purposes.

Brief description of the invention

The present invention is based on the new discovery that inhibition of SMARCA2/4 function by SMARCA2/4 degrading agents (compound of formula (I)) blocks the growth of prostate cancer cells having tumor-specific changes, including androgen receptor (AR) dependence, PTEN mutation, the presence of TMPRSS2-ERG gene fusions, caused by both inactivating mutations of the corresponding genes and loss of expression of the corresponding genes through an alternative mechanism different from inactivating mutations. The present invention provides a significant improvement over existing knowledge in the art, since at the time of filing there was no systematic approach to identify tumor-specific changes in the androgen receptor, PTEN, TMPRSS2 and ERG to predict cell susceptibility to SMARCA2/4 disrupting agents.

In one aspect, the present invention provides a method of treating prostate cancer in a subject in need thereof, comprising:

a) determining whether the subject has responded to treatment with at least one SMARCA2/4 disrupting agent, comprising the steps of:

i. isolating a biological sample from the subject;

ii. determining the presence of tumor-specific changes, where the specified tumor-specific change is: a mutation, amplification or increased expression of the androgen receptor (AR) gene;

loss-of-function mutation or deleterious mutation in phosphatase and tensin homolog (PTEN); or a genomic rearrangement that leads to translocation of the TMPRSS2 gene and the ERG gene;

iii. detecting whether the subject has responded to said treatment if at least one of the tumor-specific changes is present; And

b) administering a therapeutically effective amount of at least one SMARCA2/4 disrupting agent to a subject who has responded to treatment; wherein said SMARCA2/4 disrupting agent is a compound of formula (I):

- 2 046626

[Targeting ligand [f or a pharmaceutically acceptable salt or stereoisomer thereof;

Where

R1 is hydrogen, halogen, hydroxy(C1- _C6 )alkyl, -COORa, -CON( _Ra )2 or phenyl; wherein the phenyl is optionally independently substituted with at least one of hydroxy, (C1- _C6 )alkoxy, halogen, (C1- _C6 )alkyl, amino, -ONa, -COORa or -OCORa; wherein Ra in each case represents hydrogen or (C1-C6)alkyl;

R2 is -NH2 or -OH;

ring A is a 4-8 membered heterocycloalkyl ring or a 5-6 membered heteroaryl ring, each containing 1-2 N heteroatoms, each optionally independently substituted with at least one hydroxy;

L is a linker with the chemical structure:

wherein the left side of the linker is attached to ring A, and the right side of the linker is attached to the targeting ligand (TL);

Rb represents hydrogen;

Rc represents (C1- _C6 )alkyl;

n is from 0 to 10, and p is from 1 to 5;

the targeting ligand (TL) is:

wherein

R6 is hydrogen, (C1- _C6 )alkyl or halo(C1- _C2 )alkyl;

R7 is -O-R5 or halogen; wherein R5 represents hydrogen, (C1- _C6 )alkyl, ( _C1 - _C3 )acyl or Na; And

R8 represents hydrogen or (C1- _C4 )alkyl, providing benefits in the treatment of prostate cancer.

Brief description of the figures

Fig. 1: Effect of the SMARCA2/4 disrupting agent of the present invention in normal RWPE cells.

Fig. 2: Antiproliferative activity of the SMARCA2/4 degrading agent of the present invention in DU145 cells lacking the tumor-specific changes described herein.

Fig. 3A: Antiproliferative activity of the SMARCA2/4 disrupting agent of the present invention in 22RV1 cells that have the following tumor-specific changes:

- 3 046626 PTEN mutation (-), AR dependence (+), TMPRSS2-ERG fusion (-).

Fig. 3B: Antiproliferative activity of the SMARCA2/4 disrupting agent of the present invention in PC3 cells that have the following tumor-specific changes: PTEN mutation (+), AR dependence (-), TMPRSS2-ERG fusion (-).

Fig. 4A: Antiproliferative activity of the SMARCA2/4 degrading agent of the present invention in Vcap cells harboring the following tumor-specific alterations: PTEN mutation (-), AR dependence (+), TMPRSS2-ERG fusion (+).

Fig. 4B: Antiproliferative activity of the SMARCA2/4 disrupting agent of the present invention in LnCap cells that have the following tumor-specific changes: PTEN mutation (+), AR dependence (+), TMPRSS2-ERG fusion (-).

Detailed Description of the Invention

Each embodiment is provided to explain the invention, but not to limit the invention. Indeed, those skilled in the art will appreciate that various modifications and variations can be made to the compounds, compositions and methods described herein without departing from the scope and spirit of the invention. For example, features illustrated or described within one embodiment may be applied to another embodiment to form yet another additional embodiment. Thus, the present invention is intended to include the above modifications and changes and their equivalents. Other objects, features and aspects of the present invention will be described in the following detailed description or will become apparent upon examination thereof. It should be understood by one skilled in the art that the present discussion is provided to describe exemplary embodiments only and should not be construed as limiting the broader aspects of the present invention.

In certain embodiments, the present invention provides a method of treating prostate cancer in a subject in need thereof, comprising:

a) determining whether the subject has responded to treatment with at least one SMARCA2/4 disrupting agent, comprising the steps of:

i. isolating a biological sample from the subject;

ii. determining the presence of tumor-specific changes, where the specified tumor-specific change is:

mutation, amplification or increased expression of the androgen receptor (AR) gene;

loss-of-function mutation or deleterious mutation in phosphatase and tensin homolog (PTEN); or a genomic rearrangement that leads to translocation of the TMPRSS2 gene and the ERG gene;

iii. detecting whether the subject has responded to said treatment if at least one of the tumor-specific changes is present; And

b) administering a therapeutically effective amount of at least one SMARCA2/4 disrupting agent to a subject who has responded to treatment; wherein said SMARCA2/4 disrupting agent is a compound of formula (I):

or a pharmaceutically acceptable salt or stereoisomer thereof;

Where

R1 is hydrogen, halogen, hydroxy(C1- _C6 )alkyl, -COORa, -CON( _Ra ) ₂ or phenyl; wherein the phenyl is optionally independently substituted with at least one of hydroxy, (C1- _C6 )alkoxy, halogen, (C1- _C6 )alkyl, amino, -ONa, -COORa or -OCORa; wherein Ra in each case represents hydrogen or (C ₁ -C ₆ )alkyl;

R2 is -NH2 or -OH;

ring A is a 4-8 membered heterocycloalkyl ring or a 5-6 membered heteroaryl ring, each containing 1-2 N heteroatoms, each optionally independently substituted with at least one hydroxy;

L is a linker with the chemical structure:

- 4 046626

wherein the left side of the linker is attached to ring A, and the right side of the linker is attached to the targeting ligand (TL);

Rb represents hydrogen;

Rc represents (C1- _C6 )alkyl;

n is from 0 to 10, and p is from 1 to 5;

the targeting ligand (TL) is:

wherein

R6 is hydrogen, (C1-C ₆ )alkyl or halo(C1-C ₂ )alkyl;

R7 is -O-R5 or halogen; wherein R5 represents hydrogen, (C1- _C6 )alkyl, (C1-C3)acyl or Na; And

R8 represents hydrogen or (C1- _C4 )alkyl, providing benefits in the treatment of prostate cancer.

In certain embodiments, the present invention provides a method of treating a disease or disorder in a subject in need thereof, comprising:

a) obtaining a biological sample from the subject;

b) determining whether the subject has responded to treatment with at least one SMARCA2/4-disrupting agent if at least one tumor-specific change is present in the sample; And

c) administering a therapeutically effective amount of at least one SMARCA2/4 disrupting agent to a subject to thereby treat a disease or disorder.

In certain embodiments, the present invention provides a method of treating a disease or disorder in a subject in need thereof, wherein:

a. the subject exhibits a moderate response to treatment with SMARCA2/4 disrupting agents if there is one tumor-specific change; And

b. the subject exhibits a strong response to treatment with SMARCA2/4 disrupting agents if at least two tumor-specific changes are present.

In certain embodiments, the tumor-specific change according to the present invention is:

a) mutation, amplification or increased expression of the androgen receptor (AR) gene;

b) loss-of-function mutation or deleterious mutation of phosphatase and tensin homolog (PTEN); or

c) genomic rearrangement that leads to translocation of the TMPRSS2 and ERG genes.

In certain embodiments, the tumor-specific changes are:

loss-of-function mutation or deleterious mutation in phosphatase and tensin homologue (PTEN); and at least one of:

mutations, amplification or increased expression of the androgen receptor (AR) gene; and genome

- 5 046626 new rearrangement, which leads to translocation of the TMPRSS2 and ERG genes.

In certain embodiments, the tumor-specific changes are:

mutation, amplification or increased expression of the androgen receptor (AR) gene; and at least one of:

loss-of-function mutations or deleterious mutations in phosphatase and tensin homolog (PTEN) and genomic rearrangements that result in translocation of the TMPRSS2 and ERG genes.

In certain embodiments, the tumor-specific changes are:

genomic rearrangement that leads to translocation of the TMPRSS2 and ERG genes; and at least one of:

mutations, amplification or increased expression of the androgen receptor (AR) gene; and loss-of-function or deleterious mutations in phosphatase and tensin homolog (PTEN).

In certain embodiments, the method described in the present invention further includes determining whether a subject suffering from cancer has any one of the following factors:

mutations, amplification or increased expression of the androgen receptor (AR) gene;

loss-of-function or deleterious mutations in phosphatase and tensin homolog (PTEN); and genomic rearrangement, which leads to translocation of the TMPRSS2 AND ERG genes.

In certain embodiments, the present invention provides a method of treating a disease or disorder in a subject in need thereof, comprising:

a) determining whether the subject has responded to treatment with at least one SMARCA2/4 disrupting agent, comprising the steps of:

i. isolating a biological sample from the subject;

ii. determining the presence of tumor-specific changes; where the tumor-specific change is selected from:

mutations, amplification or increased expression of the androgen receptor (AR) gene;

loss-of-function or deleterious mutations in phosphatase and tensin homolog (PTEN); and genomic rearrangement, which leads to translocation of the TMPRSS2 and ERG genes;

iii. detecting whether the subject has responded to said treatment if at least one of the tumor-specific changes is present; And

b) administering a therapeutically effective amount of at least one SMARCA2/4 disrupting agent to a subject who has responded to treatment, thereby treating the disease or disorder.

In certain embodiments, the androgen receptor (AR) is a wild-type AR. In certain embodiments, the androgen receptor (AR) is a mutant AR.

In certain embodiments, the mutation, amplification, or increased expression of the androgen receptor (AR) gene is referred to as condition A.

In certain embodiments, a loss-of-function mutation or a deleterious phosphatase and tensin homologue (PTEN) mutation is referred to as condition B.

In certain embodiments, a genomic rearrangement that results in translocation of the TMPRSS2 and ERG genes is referred to as condition C.

In certain embodiments, tumor-specific changes, referred to as state A, also include expression of AR variants with constitutive activity, intratumor androgen synthesis, and random activation of AR by another factor. In certain embodiments, Condition A is a dysregulation (causing increased AR expression), an AR mutation (gain of function), alternative splicing (causing constitutive AR activity), gain of coactivator function or loss of corepressor function, and intracrine androgen synthesis.

In certain embodiments, Condition A is gain-of-function AR mutations or loss-of-function AR mutations.

In certain embodiments, the tumor-specific androgen receptor (AR) alteration is present in:

i. amino-terminal activation domain (NTD) of AR;

ii. DNA binding domain (DBD) AR;

iii. hinge region (HR) and (IV) AR; or iv. carboxyl ligand binding domain (LBD) of AR.

In certain embodiments, the AR gene mutations are selected from: single-point mutations resulting in amino acid substitutions or premature stop codons; nucleotide insertions or deletions, most often leading to reading frame shifts and premature rumination; complete or partial gene deletions; and intronic mutations causing alternative splicing.

In certain embodiments, the tumor-specific androgen receptor alteration is RNA-based androgen receptor (AR) splice variants (AR-V), including, but not limited to, AR-V1, AR-V2, AR-V3, AR-V4 , AR-V5, AR-V6, AR-V7, AR

- 6 046626

V567es, AR-V9 or AR-V12, together with additional tumor-specific changes, including, but not limited to, DNA and/or RNA mutations, insertion deletion mutations, copy number changes, gene fusions in biological samples, such as plasma , serum, urine, saliva, etc.

In certain embodiments, the mutant AR is a splice variant and/or a truncated AR. In additional embodiments, the mutant AR may be a splice variant and/or a truncated AR that is missing a moiety at the C-terminus and therefore the ligand binding domain (LBD). Examples of mutations include, for example, K43G, L54S, Q58L, L57Q, Q64R, AQ86, QI 12H, G142V, E166S, K180R, L192F, Q198G, E211E, D221H, N222D, T227C, M266T, P269S, A251V, , S296R, P334F , P340L, A356V, P390L, G414S, W433L, T438P, T438I, L444S, G449D, G451D, G456S, G457D, R484C,

T497I, A498T, P499P, V508L, G524S, G524D, D528G, AL547, ΔΡ554, T573A, L574P, K580R, A586V, A587S, L594M, K609E, R629Q, K630T, S646D, S647N, 665D, Q670R, I672T, G683A, V716M, V715M, L701H, L720E, A721T, V730M, R726L, L744V, A748V, M749I, G750S, F754L, T755A, V757A, S759P, Y763C, W741C, F747L, N756A, V757I, R760K, 1X, AG743, W751X, S782N, R786X, W796O, L797P, Q798E, S791P, I799P, L830P, R846G, Q867X, H874Y, T877A, T877S, V866M, L880Q, L872P, D879G, M886I, A896T, Q902R, F891L, G909Q, 9R, D890N, M895V and K910R.

For example, amino acid substitutions are:

T877A (T878A), D879G (D878G), W741C, W741L, M749L, R629Q, G142V, P533S, T575A, H874Y or F876L.

These point mutations can be attributed to three main regions of the steroid receptor protein:

1) LBD mutants (T877A, D879G, W741C, W741L, M749L, H874Y, F876L) and LBD mutations may have altered ligand binding due to conformational changes in the receptor protein or changes in R-groups in amino acids in the ligand-binding pocket or a conformation in which it is not possible ligand binding, loss of ligand recognition, switch of function from antagonist to agonist and/or ligand nonspecificity;

2) NTD or hinge region mutants (R629Q, G142V, P533S), which may affect receptor transactivation ability, interaction with transcriptional machinery, or cofactors/regulators and lead to changes in receptor functions such as DNA binding, regulation of gene expression, or nuclear translocation; or

3) DBD mutants (T575A), which can affect the receptor's ability to regulate gene expression. Examples include: the H874Y mutation in the androgen receptor, which has been shown to mediate the binding of estradiol, progesterone, hydrocortisone, flutamide and bicalutamide in 22Rv1 and CWR22RV1 cells; D878G, which has been shown to result in loss of DHT and testosterone binding and activity; the W741C mutations, which confer agonist functions on bicalutamide and flutamide; F876L, which switches the functions of ARN-509 and enzalutamide from antagonists to agonists; M749L, which confers increased susceptibility to estradiol; T575A, which leads to preferential binding to AR-nonspecific motifs, i.e. GRE; R629Q, which leads to the acquisition of DHT function.

In certain embodiments, splice variants include exon skipping, use of a donor/acceptor for cryptic splicing, and cryptic exon inclusion. Variants identified include AR-V1, AR-V2, AR-V3, AR-V4, AR-V5, AR-V6, ARV7, AR-V567es, AR-V7, AR-V9, AR-V12, AR-V13 and AR -V14. (See, for example, US Patent Application No. 2011/0110926, US Patent No. 8133724, and US Patent Application No. 2013/0130241). In general, androgen receptor variants lack some or all of the LBD and/or that portion of the carboxyl terminus of the androgen receptor protein that mediates ligand binding.

In other embodiments, the tumor-specific AR change is ART878A or other similar mutation, copy number gain, increased RNA expression, among others.

In certain embodiments, the AR gene mutations are single-point mutations. In some other embodiments, the mutant AR may have a point mutation, such as T877A (T878A), D879G, (D878G), W741C, W741L, M749L, R629Q, G142V, P533S, T575A, H874Y, or F876L.

In certain embodiments, the present invention provides a method comprising: testing for the presence of one or more splice variants of the androgen receptor gene (ARV) and additional tumor-specific changes, such as mutation, insertion-deletion

- 7 046626 mutations, copy number changes, gene fusions, etc. in a biological sample of the subject.

In certain embodiments, the tumor-specific change according to the present invention includes AR amplification. In certain embodiments, AR amplification is a tumor-specific change that occurs as a result of androgen deprivation therapy. This AR amplification may sometimes be associated with increased AR expression.

In certain embodiments, the tumor-specific change is a loss of function mutation in the PTEN gene.

In certain embodiments, mutations in the PTEN gene include mutations in exon 1, exon 2, exon 3, exon 4, exon 5, exon 6, exon 7, exon 8, or exon 9. In certain embodiments, mutations in the PTEN gene include

G20STOP, R55G, T38G, E91Q, R387STOP, H118Y, 1101 A, I135V, Q150G, Q110STOP,

P95S, A164STOP, 564, c.761-765del, c.672-673Ins, c.224Ins, D223N, E201STOP,

D326N, H272Y, T348I, K344R or T382S.

In certain embodiments, mutations in the PTEN gene include mutations in exon 5 or exon 8. In certain embodiments, mutations in the PTEN gene include

E91Q, R387STOP, H118Y, 1101 A, I135V, Q150G, QllOSTOP, P95S,

A164STOP, E201STOP, D326N or H272Y.

In certain embodiments, the tumor-specific alteration of the present invention is a fusion gene having a 5' portion of an androgen-regulated gene (ARG) transcriptional regulatory region and a 3' portion of a gene that is a member of the ETS family, where the presence of the fusion gene is an indicator of cancer prostate gland in the subject.

In certain embodiments, the androgen-regulated gene (ARG) is TMPRSS2 or PSA. In certain specific embodiments, the androgen-regulated gene (ARG) is TMPRSS2.

In certain embodiments, the gene that is a member of the ETS family is ERG, ETV1 (ER81), FLU, ETS1, ETS2, ELK1, ETV6 (TEL1)5,

ETV7 (TEL2), GABPa, ELF1, ETV4 (E1AF; PEA3), ETV5 (ERM), ERF, PEA3/E1AF,

PU.l, ESE1/ESX, SAP1 (ELK4), ETV3 (METS), EWS/FLI1, ESEI, ESE2 (ELF5), ESE3, PDEF, NET (ELK3; SAP2), NERF (ELF2) or FEV

In certain embodiments, the gene that is a member of the ETS family is an ERG.

In certain embodiments, a fusion gene having a 5' portion of an androgen-regulated gene (ARG) transcriptional regulatory region and a 3' portion of an ETS family member gene causes increased ERG expression in the prostate gland.

In some embodiments, the biological sample is a sample of blood, plasma, serum, urine, sputum, cerebrospinal fluid, cerebrospinal fluid, pleural fluid, nipple secretions, lymphatic fluid, respiratory tract fluid, intestinal and genitourinary tract fluid, tear fluid, saliva, breast milk , fluid from the lymphatic system, seminal fluid, cerebrospinal fluid, intraorgan fluid, ascitic fluid, tumor cyst fluid, amniotic fluid, or a combination thereof. In one embodiment, the biological sample is a sample of blood, plasma, serum, urine, sputum, cerebrospinal fluid, cerebrospinal fluid, pleural fluid, lymphatic fluid, respiratory tract fluid, intestinal and genitourinary tract fluid, saliva, lymphatic system fluid, seminal fluid , cerebrospinal fluid, ascitic fluid, tumor cyst fluid, amniotic fluid, or a combination thereof.

In certain embodiments, tumor-specific changes according to the present invention are determined by methods including, but not limited to, next generation sequencing (NGS), immunohistochemistry, mass spectrometry (MS), liquid chromatography-mass spectrometry (LC-MS), quantitative PCR , RNA sequencing (RNA-seq) or fluorescence-activated cell sorting (FACS) analysis, fluorescence in situ hybridization (FISH). In certain embodiments, tumor-specific changes are determined by next generation sequencing (NGS).

In certain embodiments, the present invention provides a method of treating prostate cancer in a subject in need thereof, comprising:

a) obtaining a biological sample from the subject;

b) determining whether the subject has responded to treatment with at least one SMARCA2/4-disrupting agent if at least one tumor-specific change is present in the sample; And

c) administering a therapeutically effective amount of at least one SMARCA2/4 disrupting agent to a subject to thereby treat prostate cancer.

- 8 046626

In certain embodiments, the present invention provides a method of treating a disease or disorder in a subject in need thereof, comprising:

a) determining whether the subject has responded to treatment with at least one SMARCA2/4 disrupting agent in combination with another therapeutic agent, comprising the steps of:

i. isolating a biological sample from the subject; ii. determining the presence of tumor-specific changes;

iii. detecting whether the subject has responded to said treatment if at least one of the tumor-specific changes is present; And

b) administering a therapeutically effective amount of at least one SMARCA2/4 disrupting agent to a subject who has responded to treatment, thereby treating the disease or disorder.

In one embodiment, potential therapeutic agents include, but are not limited to, biological agents, immune checkpoint modulators, and chemotherapeutic agents, such as cytotoxic agents.

As used herein, an immune checkpoint modulator is an antagonist molecule that has an antagonistic effect on the activity of PD-1, PD-L1 or CTLA-4. Examples of immune checkpoint modulators include, but are not limited to:

i. PD-1 inhibitors such as pembrolizumab (formerly MK-3475 or lambrolizumab, Keytruda®), nivolumab (Opdivo®), pidilizumab, AMP-224, AMP-514, PDR001 and cemiplimab.

ii. PD-L1 inhibitors such as atezolizumab (Tecentriq®), avelumab (Bavencio®), durvalumab (Imfinzi®), BMS-936559, CK-301 (Iwai, et al, Journal of Biomedical Science, (2017) 24:26) .

iii. CTLA4 antagonists such as ipilimumab, also called MDX-010 or MDX-101, an anti-human CTLA4 antibody, preferably administered at a dose of about 10 mg/kg, and tremelimumab, an anti-human CTLA4 antibody, preferably administered at a dose of about 15 mg/kg. See also Sammartino, et al, Clinical Kidney Journal, 3(2): 135-137 (2010), published online December 2009.

In one embodiment, the chemotherapeutic agent is a chemical compound suitable for treating cancer. In one embodiment, the compounds of the present invention, or a pharmaceutically acceptable composition containing them, are administered in combination with a chemotherapeutic agent, including erlotinib (TARTCEVA®, Genentech/OSI Pharm.), bortezomib (VELCADE®, Millennium Pharm.), disulfiram, epigallocatechin gallate, salinosporamide A, carfilzomib, 17-AAG (geldanamycin), radicicol, lactate dehydrogenase A (LDH-A), fulvestrant (FAZLODEX®, AstraZeneca), sunitinib (SUTENT®, Pfizer/Sugen), letrozole (FEMARA®, Novartis), imatinib mesylate (GLIVEC®., Novartis), finasunate (VATALANIB®, Novartis), oxaliplatin (ELOXATIN®, Sanofi), 5-FU (5-fluorouracil), leucovorin, rapamycin (sirolimus, RAPAMUNE®, Wyeth), lapatinib (TYKERB®, GSK572016, Glaxo Smith Kline), lonafamib (SCH 66336), sorafenib (NEXAVAR®, Bayer Labs), gefitinib (IRESSA®, AstraZeneca), AG1478, alkylating agents such as thiotepa and CYTOXAN®, cyclophosphamide; alkylsulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa and uredopa; ethyleneimines and methylamelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylolmelamine; acetogenins (in particular bullatacin and bullatacinone); camptothecin (including topotecan and irinotecan); bryostatin; kallistatin; CC-1065 (including its synthetic analogues adozelesin, carzelesin and bizelesin); cryptophycins (in particular cryptophycin 1 and cryptophycin 8); adrenocorticosteroids (including prednisone and prednisolone); cyproterone acetate; 5a-reductases, including finasteride and dutasteride; vorinostat, romidepsin, panobinostat, valproic acid, mocetinostat, dolastatin; aldesleukin, talc duocarmycin (including synthetic analogues KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictyin;

spongistatin; nitrogen mustards, such as chlorambucil, chlomafazin, chlorphosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembiquin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorosotocin, fotemustine, lomustine, nimustine and ranimustine; antibiotics such as enediyne antibiotics (eg calicheamicin, particularly calicheamicin/ ¹ ! and calicheamicin coll (Angew Chem. Intl. Ed. Engl. 1994 33: 183-186); dinemycin, including dinemycin A; bisphosphonates such as clodronate ; esperamycin; as well as the chromophore neocarcinostatin and related chromoproteinenediine antibiotic chromophores), aclacinomycin, actinomycin, autramycin, azaserin, bleomycin, cactinomycin, carabicin, carminomycin, carcinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-E -norleucine, ADRIAMICIN® (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxidoxorubicin), epirubicin, ezorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin,

- 9 046626 olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rhodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprin, thioguanine; pyrimidine analogs such as ancesitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocytabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epithiostanol, mepithiostane, testolactone; drugs that suppress adrenal function, such as aminoglutethimide, mitotane, trilostane; a folic acid replenishing agent such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatrexate; defofamine; demecolcine; diaziquon; elfomitin; elliptinium acetate; epothilone; ethoglucide; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; methoxantrone; mopidamnol; nitraerin; pentostatin; phenameth; pirarubicin; losoxantrone; polophyllic acid; 2-ethylhydrazide; procarbazine; polysaccharide complex PSK® (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sisofuran; spirogermania; tenuazonic acid; triaziquon; 2,2',2trichlorotriethylamine; trichothecenes (in particular, T-2 toxin, verracurin A, roridin A and anguidine); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (Ara-C); cyclophosphamide; thiotepa; taxoids, such as TAXOL (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE® (without Cremophor), nanoparticle formulations of paclitaxel made using albumin (American Pharmaceutical Partners, Schaumberg, 111.) and TAXOTEROME® (docetaxel, doxetaxel; Sanofi-Aventis); chlorambucil; GEMZAROM® (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogues such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; BLACKED® (vinorelbine); novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA®); ibandronate; SRT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the above agents.

In one embodiment, the biological agents include antibodies such as alemtuzumab (Kampat), bevacizumab (ABASTEST®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (BECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen Idee), pertuzumab (OMNITARG®, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexar, Corixia) and antibody-drug conjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth). Additional humanized monoclonal antibodies that have therapeutic potential as agents when used in combination with compounds of the invention include: apolizumab, aselizumab, atlizumab, bapineizumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, umab, efalizumab , epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizumab, numavizumab, omalizumab, palivizumab, pascolizumab, pecfusitumumab, pectuzumab, pexelizumab , ralivizumab, ranibizumab, reslivizumab, reslizumab, recivizumab, rovelizumab, ruplizumab, sibrotuzumab, siplizumab, sontuzumab, takatuzumab tetraxetane, tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab, tucotuzumab celmoleukin tucusit, uzumab, umavizumab, urtoxazumab, ustekinumab, visilizumab and anti-interleukin -12 (ABT-874L695, Wyeth Research and Abbott Laboratories), which is a recombinant full-length IgGi λ antibody with exclusively human sequence, genetically modified to recognize the interleukin-12 p40 protein.

In certain embodiments, the present invention provides methods for inhibiting the progression, reduction in size, accumulation, volume reduction, and/or other suppression of tumor growth using at least one SMARCA2/4 disrupting agent. Also provided herein are methods of treating an underlying disease, such as prostate cancer, and thereby prolonging the survival of a subject.

In certain embodiments, the present invention provides a method of inhibiting tumor growth in a subject who has responded to treatment with a SMARCA2/4 degrading agent in need thereof, the method comprising administering to the subject an effective amount of a SMARCA2/4 degrading agent.

In certain embodiments, the present invention provides a method of suppressing tumor growth, wherein tumor growth is reduced by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12% , 14%, 16%, 18%, 20%, 22%, 24%, 26%, 28%, 30%, 32%, 34%, 36%, 38%, 40%, 42%, 44%, 46 %, 48%, 50%, 52%, 54%, 56%, 58%, 60%, 62%, 64%, 66%, 68%, 70%, 72%, 74%, 76%, 78%, 80%, 82%, 84%, 86%, 88%, 90%,

- 10 046626

92%, 94%, 96%, 98% or 100% when measured based on tumor volume.

In certain embodiments, the present invention provides a method of inhibiting tumor growth, wherein tumor growth is reduced by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12% , 14%, 16%, 18%, 20%, 22%, 24%, 26%, 28%, 30%, 32%, 34%, 36%, 38%, 40%, 42%, 44%, 46 %, 48%, 50%, 52%, 54%, 56%, 58%, 60%, 62%, 64%, 66%, 68%, 70%, 72%, 74%, 76%, 78%, 80%, 82%, 84%, 86%, 88%, 90%, 92%, 94%, 96%, 98%, or 100% when measured based on absolute tumor size.

In certain embodiments, the present invention provides a method of inhibiting tumor growth, wherein tumor growth is reduced by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12% , 14%, 16%, 18%, 20%, 22%, 24%, 26%, 28%, 30%, 32%, 34%, 36%, 38%, 40%, 42%, 44%, 46 %, 48%, 50%, 52%, 54%, 56%, 58%, 60%, 62%, 64%, 66%, 68%, 70%, 72%, 74%, 76%, 78%, 80%, 82%, 84%, 86%, 88%, 90%, 92%, 94%, 96%, 98%, or 100% when measured based on tumor marker expression levels of a given tumor type.

In certain embodiments, the present invention provides a method for inhibiting the growth of prostate cancer. In specific embodiments, the present invention provides a method for inhibiting the growth of castration-resistant prostate cancer.

Accordingly, the present invention also provides a method of treating prostate cancer in a subject in need thereof who has responded to treatment with SMARCA2/4 degrading agents, the method comprising administering an effective amount of a SMARCA2/4 degrading agent to the subject.

In certain embodiments, methods of treating prostate cancer or castration-resistant prostate cancer are described.

Androgen receptor activity and gene expression profile in prostate cancer were studied. The search for a biomarker begins by identifying an up-regulated gene and testing the said gene product as a potential biomarker. Gene expression profiling and the relationship of expression to the mechanism of therapeutic resistance is described in Holzbeierlein et al, Am. J.Path. 164(1), pp.217-227, 2004. Despite the identification of increased or decreased expression of certain genes, genomic changes in certain genes can occur in prostate cancer, including: rearrangement (transcription factors ETS, RAF, KRAS); mutation (androgen receptor, P1K3SA, AKT, RAF, KRAS); amplification (androgen receptor, P1K3SA, MYC, AURKA); loss (PTEN, RBI). Other known tumor-specific changes occur in the SPOP, FOXA1, AURKA, MED 12, MAGI-1, and CHD1 genes. ETS fusions can be detected in more than 50% of PrCa cases, and targeted therapy or biomarker, such as targeted PARP or DNAPK inhibition or testing for the presence of ETS fusions in patient samples, can be used. Expression of oncogene, RAS/RAF, MYC, as well as the tumor suppressor gene RBI may be suitable biomarkers.

The androgen receptor is known to regulate a large repertoire of genes that determine the identity and behavior of prostate cancer cells. Increased expression of long non-coding RNAs, such as PCGEM1 and PRNCR1, is associated with and correlates with prostate cancer susceptibility. Recently, highly elevated expression of both PCGEM1 and PRNCR1 has been described in CRPC, and they bind and activate both ligand-dependent and ligand-independent AR-mediated activation programs and may lead to uncontrolled proliferation of prostate cancer cells. (Yang et al. Nature 2013, 500(7464):598-602).

In certain embodiments, the present invention provides a method of treating a disease or disorder in a subject in need thereof; wherein said disease or disorder includes at least one of tumor-specific changes selected from:

a) mutation, amplification or increased expression of the androgen receptor (AR) gene;

b) loss-of-function mutations or deleterious mutations in phosphatase and tensin homolog (PTEN); and c) a genomic rearrangement that results in translocation of the TMPRSS2 and ERG genes.

In certain embodiments, the subject suffers from prostate disease.

In certain embodiments, the prostate disease is prostate cancer.

In certain embodiments, the prostate disease is castration-resistant prostate cancer.

In certain embodiments, the subject is castrated.

In certain embodiments, the subject is administered antiandrogen therapy.

In a specific embodiment, the present invention provides a method of selecting a subject suffering from prostate disease for treatment with a SMARCA2/4 disrupting agent, comprising:

a) obtaining a biological sample from the subject;

b) determining the presence of at least one tumor-specific change in the biological sample;

c) selecting a subject whose sample contains at least one tumor-specific change

- 11 046626 nenie, for treatment with an agent that destroys SMARCA2/4; And

d) administering a therapeutically effective amount of at least one SMARCA2/4 disrupting agent to the selected subject.

Compounds used in the present invention.

In certain embodiments, the present invention provides a method of treating a disease or disorder in a subject in need thereof who has responded to treatment according to the methods described herein, comprising administering to the subject a therapeutically effective amount of a SMARCA2/4 disrupting agent; wherein the SMARCA2/4 degrading agent is represented by a compound of formula (I):

ligand I (I) or a pharmaceutically acceptable salt or stereoisomer thereof; Where

R ₁ is hydrogen, halogen, alkyl, alkenyl, alkoxy, hydroxy, hydroxyalkyl, -COORa, -CON(R _a ) ₂ or aryl; wherein aryl is optionally substituted with at least one of hydroxy, alkoxy, halogen, alkyl, amino, -ONa, -COOR _a and -OCOR _a ; wherein R _{a is} in each case selected from hydrogen and alkyl;

R2 is -NR3R ₄ or OR3; wherein R3 and _R4 are independently selected from hydrogen and alkyl;

ring A is a heterocyclic ring, optionally substituted with at least one of hydroxy, halogen and alkyl;

L is a linker with the chemical structure:

wherein the left side of the linker is attached to ring A, and the right side of the linker is attached to the targeting ligand (TL);

Rb represents hydrogen or alkyl; Rc represents alkyl; n is from 0 to 10, and p is from 1 to 5; targeting ligand (TL) is

wherein

R6 is selected from hydrogen, alkyl, acyl and haloalkyl;

R7 is selected from -O-R5 and halogen; wherein R5 is selected from hydrogen, alkyl, acyl and Na; And

R8 represents hydrogen or alkyl.

In yet another embodiment, the present invention provides a method of treating a disease or disorder in a subject in need thereof who has responded to treatment according to the methods described herein, comprising administering to the subject a therapeutically effective amount of a SMARCA2/4 disrupting agent; wherein the SMARCA2/4 disrupting agent is represented by compounds of formula (IA):

- 12 046626

or pharmaceutically acceptable salts or stereoisomers thereof;

where R1, ring A, L and the targeting ligand are as defined for formula (I).

In yet another embodiment, the present invention provides a method of treating a disease or disorder in a subject in need thereof who has responded to treatment according to the methods described herein, comprising administering to the subject a therapeutically effective amount of a SMARCA2/4 disrupting agent;

wherein the SMARCA2/4 disrupting agent is represented by compounds of formula (IB):

or pharmaceutically acceptable salts or stereoisomers thereof; wherein ring A, L and targeting ligand are as defined for formula (I).

In yet another embodiment, the present invention provides a method of treating a disease or disorder in a subject in need thereof who has responded to treatment according to the methods described herein, comprising administering to the subject a therapeutically effective amount of a SMARCA2/4 disrupting agent;

wherein the SMARCA2/4 degrading agent is represented by compounds of formula (IC):

or pharmaceutically acceptable salts or stereoisomers thereof; where L and the targeting ligand are as defined for formula (I).

In yet another embodiment, the present invention provides a method of treating a disease or disorder in a subject in need thereof who has responded to treatment according to the methods described herein, comprising administering to the subject a therapeutically effective amount of a SMARCA2/4 disrupting agent;

wherein the SMARCA2/4 disrupting agent is represented by compounds of formula (ID):

or pharmaceutically acceptable salts or stereoisomers thereof; where L and the targeting ligand are as defined for formula (I).

In certain embodiments of the methods described herein, the SMARCA2/4 disrupting agent is a compound of the chemical structure:

- 13 046626

- 14 046626

- 18 046626

- 19 046626

- 20 046626

- 21 046626

- 22 046626

- 23 046626

- 24 046626

- 25 046626

- 26 046626

- 27 046626

- 28 046626

- 29 046626

- 30 046626

- 31 046626

- 32 046626

- 33 046626

- 34 046626

or a pharmaceutically acceptable salt or stereoisomer thereof.

In certain embodiments, the present invention provides a method of selecting a patient suffering from prostate cancer for treatment with a SMARCA2/4 disrupting agent, comprising:

a) obtaining a biological sample from the patient;

b) determining the possible presence of one or more tumor-specific changes; And

c) selecting a patient whose sample contains at least one tumor-specific alteration for treatment with an agent that disrupts SMARCA2/4.

- 35 046626

In certain embodiments, the present invention provides a method of selecting a subject suffering from prostate cancer for treatment with a SMARCA2/4 disrupting agent, comprising:

a) obtaining a biological sample from the patient;

b) determining the possible presence of one or more tumor-specific changes; And

c) selecting a patient whose sample contains at least one tumor-specific alteration for treatment with an agent that disrupts SMARCA2/4; And

d) treating the selected patient with a therapeutically effective amount of at least one SMARCA2/4 disrupting agent.

In certain embodiments, the present invention provides a method of selecting a patient suffering from prostate cancer for treatment with a SMARCA2/4 disrupting agent, comprising:

a) obtaining a biological sample from the patient;

b) determining the possible presence of one or more tumor-specific changes; where tumor-specific changes include:

mutation, amplification or increased expression of the androgen receptor (AR) gene;

loss-of-function mutation or deleterious mutation in phosphatase and tensin homolog (PTEN); or a genomic rearrangement that leads to translocation of the TMPRSS2 and ERG genes; And

c) selecting a patient whose sample contains at least one tumor-specific alteration for treatment with an agent that disrupts SMARCA2/4.

In certain embodiments, the present invention provides a method of selecting a patient suffering from prostate cancer for treatment with a SMARCA2/4 disrupting agent in combination with another therapeutic agent, comprising:

a) obtaining a biological sample from the patient;

b) determining the possible presence of one or more tumor-specific changes; And

c) selecting a patient whose sample contains at least one tumor-specific alteration for treatment with a SMARCA2/4 disrupting agent in combination with another therapeutic agent; And

d) treatment with a therapeutically effective amount of at least one SMARCA2/4 disrupting agent in combination with another therapeutic agent in the selected patient.

In certain embodiments, the present invention provides a method of selecting a subject suffering from prostate disease for treatment with an agent that destroys SMARCA2/4, which method is carried out in vitro.

In one embodiment, the present invention provides a method of inhibiting the proliferation of prostate cancer cells in a subject, comprising:

i. collecting a biological sample from the subject;

ii. determining the presence of tumor-specific changes selected from:

mutations, amplification or increased expression of the androgen receptor (AR) gene;

loss-of-function or deleterious mutations in phosphatase and tensin homolog (PTEN); and genomic rearrangement, which leads to translocation of the TMPRSS2 gene and the ERG gene;

iii. administering a therapeutically effective amount of at least one SMARCA2/4 disrupting agent to a subject if the subject has at least one of the tumor-specific changes.

In certain embodiments, the present invention provides a method of inhibiting the proliferation of prostate cancer cells, comprising the step of contacting the prostate cancer cells with at least one SMARCA2/4 degrading agent; wherein the SMARCA2/4 degrading agent is represented by a compound of formula (I).

In certain embodiments, the present invention provides a method of inhibiting the proliferation of prostate cancer cells having one or more tumor-specific changes, comprising the step of contacting the prostate cancer cells with at least one SMARCA2/4 disrupting agent; wherein the SMARCA2/4 degrading agent is represented by a compound of formula (I).

In certain embodiments, the present invention provides a method of inhibiting the proliferation of prostate cancer cells, comprising the step of contacting the prostate cancer cells with at least one SMARCA2/4 degrading agent; where the agent that destroys SMARCA2/4 is a compound described in table. A.

In certain embodiments, the present invention provides a method of inhibiting the proliferation of prostate cancer cells having one or more tumor-specific changes, comprising the step of contacting the prostate cancer cells with at least one SMARCA2/4 disrupting agent; where the SMARCA2/4 disrupting agent is a compound described in table. A.

- 36 046626

In certain embodiments, the present invention provides a method of inhibiting the proliferation of prostate cancer cells, wherein the prostate cancer cells comprise a prostate tumor present in a subject.

In certain embodiments, the present invention provides a method for inhibiting the proliferation of prostate cancer cells, wherein the method is conducted in vitro.

In certain embodiments, the present invention provides a method of selecting a subject suffering from prostate disease for treatment with a SMARCA2/4 disrupting agent, comprising:

a) obtaining a biological sample from the subject;

b) determining the possible presence of one or more tumor-specific changes in the biological sample;

c) selecting a subject in whose sample at least one tumor-specific alteration is present for treatment with an agent that disrupts SMARCA2/4; And

d) treating the selected subject with a therapeutically effective amount of at least one SMARCA2/4 disrupting agent.

In certain embodiments, the present invention provides a method of selecting a subject suffering from prostate disease for treatment with a SMARCA2/4 disrupting agent in combination with another therapeutic agent, comprising:

a) obtaining a biological sample from the subject;

b) determining the possible presence of one or more tumor-specific changes in the biological sample;

c) selecting a subject in whose sample at least one tumor-specific alteration is present for treatment with a SMARCA2/4 disrupting agent in combination with another therapeutic agent; And

d) treatment with a therapeutically effective amount of at least one SMARCA2/4 disrupting agent in combination with another therapeutic agent in the selected subject.

In certain embodiments, the SMARCA2/4 disrupting agent is a compound of formula (IA), (IB), (IC), or (ID):

or a pharmaceutically acceptable salt or stereoisomer thereof.

In certain embodiments, the present invention provides a compound for use in a method for selecting a subject suffering from prostate cancer, the compound being a compound of formula (I):

or a pharmaceutically acceptable salt or stereoisomer thereof; Where

R1 is hydrogen, halogen, alkyl, alkenyl, alkoxy, hydroxy, hydroxyalkyl, -COORa, -CON(R _a ) ₂ or aryl; wherein aryl is optionally independently substituted with at least one of hydroxy, alkoxy, halogen, alkyl, amino, -ONa, -COORa or -OCORa; wherein Ra in each case represents hydrogen or alkyl;

- 37 046626

R2 is -NR3R4 or -OR3; wherein R3 and R4 are independently hydrogen or alkyl;

ring A is a heterocyclic ring, optionally independently substituted with at least one of hydroxy, halogen or alkyl;

L is a linker with the chemical structure:

wherein the left side of the linker is attached to ring A, and the right side of the linker is attached to the targeting ligand (TL);

Rb represents hydrogen or alkyl; Rc represents alkyl; n is from 0 to 10, and p is from 1 to 5; targeting ligand (TL) is

YOU · TL-2 _or TL-3 in this case

R6 is hydrogen, alkyl, acyl or haloalkyl;

R7 is -OR ₅ or halogen; wherein R ₅ represents hydrogen, alkyl, acyl or Na; And

R8 represents hydrogen or alkyl.

In certain embodiments, the compound for use in a method of selecting a subject suffering from prostate cancer is a compound represented by a compound of formula (IA):

or a pharmaceutically acceptable salt or stereoisomer thereof.

In certain embodiments, the compound for use in a method of selecting a subject suffering from prostate cancer is a compound represented by a compound of formula (IB):

or a pharmaceutically acceptable salt or stereoisomer thereof.

In certain embodiments, the compound for use in a method of selecting a subject suffering from prostate cancer is a compound represented by a compound of formula (IC):

- 38 046626

or a pharmaceutically acceptable salt or stereoisomer thereof.

In certain embodiments, the compound for use in a method of selecting a subject suffering from prostate cancer is a compound represented by a compound of formula (ID):

or a pharmaceutically acceptable salt or stereoisomer thereof.

Definitions

It should be noted that in the present specification and the accompanying claims, the singular forms (corresponding to the English articles a, an and the) include the plural unless the context clearly requires otherwise. Thus, for example, a description of a biomarker includes a mixture of two or more biomarkers, etc.

As used herein, the terms contains, contains, comprises, includes, has, having, and any forms thereof, are intended to cover non-exclusive inclusion, such that a process, method, product manufactured by a particular method, or composition that contains, includes or has an element or list of elements that does not exclusively include the specified elements, but may also include other elements not expressly listed or inherent in the specified process, method, product manufactured by a particular method, or composition.

As used herein, the term tumor-specific changes refers to any genomic change that results in a change in DNA sequence, mRNA sequence, protein sequence, changes in gene expression (affecting the amount of both mRNA and protein), or combinations thereof. Tumor-specific changes include, but are not limited to, deleterious mutations (eg, mutations that reduce or eliminate either gene function or gene expression), loss-of-function mutations, gain-of-function mutations, etc. Tumor-specific changes involve insertions of viral genetic material into the genome of infected host cells (eg, human papillomavirus). Tumor-specific changes include microsatellites or other repetitive regions of DNA (eg, short tandem repeats or simple sequence repeats).

As used herein, the phrase gain-of-function mutation, with respect to a particular gene or gene product, refers to a type of mutation in which the altered gene product acquires a new molecular function or a new gene expression profile.

As used herein, a loss-of-function (LOF) mutation refers to a mutation or allele of a gene whereby the gene product (such as an encoded protein) has reduced or no function in a cell or organism (including a human cell or organism) function. If an allele has a complete loss of function (null allele), it is often called an amorphous mutation. Phenotypes associated with loss-of-function mutations are often recessive.

As used herein, the term increased expression when describing a gene (eg, an oncogenic driver gene) refers to any increase in the level of protein mRNA or combinations thereof corresponding to the gene compared to normal. For example, the term increased AR gene expression refers to any increase in the mRNA level, protein level, or combinations thereof corresponding to the AR gene.

As used herein, the term genomic rearrangement of the TMPRSS2 and ERG genes refers to any rearrangement of the TMPRSS2 and ERG genes that is associated with prostate cancer, and may include a fusion of the TMPRSS2 and ERG genes. This genomic rearrangement can lead to translocation of the TMPRSS2 and ERG genes.

As used herein, the term therapeutically effective amount of a pharmaceutical agent or combination of agents is intended to refer to an amount of agent(s) that provides a therapeutic effect in a subject being treated, at an acceptable benefit/risk ratio that applies to any drug treatment. The therapeutic effect can be objective (ie, can be measured in some study or using a marker) or subjective (ie, the subject himself reports the effect or feels the indicated effect). A therapeutically effective amount is typically administered as part of an administration regimen, which may include multiple unit doses. For any given pharmaceutical agent, a therapeutically effective co

- 39 046626 the quantity (and/or the corresponding dose within an effective administration regimen) may vary, for example, depending on the route of administration, combination with other pharmaceutical agents. In addition, the specific therapeutically effective amount (and/or unit dosage) for any particular subject may depend on various factors, including the disorder being treated and the severity of the disorder; the activity of the particular pharmaceutical agent used; the specific composition used; age, body weight, general health, gender, and diet of the subject; time of administration, route of administration, and/or rate of elimination or metabolism of the particular pharmaceutical agent employed; duration of treatment; and similar factors well known in the medical field.

As used herein, the term treatment (as well as treat or method of treatment) refers to any administration of a pharmaceutical agent, drug or drug that partially or completely attenuates, reduces, alleviates, suppresses, delays the onset of, reduces the severity of and/or reduces the incidence of one or more symptoms or hallmarks of a particular disease, disorder, syndrome and/or condition. The treatment may be administered to a subject who does not experience signs of the corresponding disease, disorder and/or condition, and/or to a subject who experiences only early signs of the disease, disorder and/or condition. Alternatively or in addition, the treatment may be administered to a subject who experiences one or more established signs of the respective disease, disorder and/or condition.

As used herein, the terms optional or optional mean that the event or condition described below may or may not occur (occur), and the description includes cases in which the specified event or condition occurs (satisfied) as well as cases in which in which it does not occur (is not executed). For example, optionally substituted alkyl refers to an alkyl that may be substituted, as well as an event or condition in which the alkyl is not substituted.

The term substituted refers to moieties containing substituents that replace a hydrogen atom at one or more backbone carbon atoms. It should be understood that substitution or substituted includes the implied condition that said substitution corresponds to the permitted valency of the substituted atom and substituent, and that said substitution results in the formation of a stable compound, for example, which does not undergo spontaneous transformation, for example, by rearrangement, cyclization, elimination, etc. .d. As used herein, the term substituted is intended to include all acceptable substituents for organic compounds. In broad terms, acceptable substituents include acyclic and cyclic, branched and straight-chain, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. One or more acceptable substituents may be present in the corresponding organic compounds, which may be the same or different. For purposes of the present invention, heteroatoms, such as nitrogen, may contain hydrogen substituents and/or permissible organic substituents described herein that satisfy the valency rule for heteroatoms. Substituents may include any of the substituents described herein, for example, halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl or acyl), thiocarbonyl (such as thioester, thioacetate or thioformate), alkoxy, oxo, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heteroaryl, heterocycloalkyl, aralkyl, or an aromatic or heteroaromatic moiety. Those skilled in the art will appreciate that the substituents themselves may, where appropriate, be substituted. The descriptions herein of chemical moieties that are not specifically designated as unsubstituted include substituted variants. For example, the description of an aryl group or moiety implicitly includes both substituted and unsubstituted variants.

As used herein, the term alkyl refers to saturated aliphatic groups, including, but not limited to, C1-C10 linear alkyl groups or C3-C10 branched alkyl groups. Preferably, the alkyl group is a Ο ₁ -Ο ₆ linear alkyl group or a C ₃ -C ₆ branched alkyl group. Most preferably, the alkyl group is a C1- _C4 linear alkyl group or a _C3 - _C8 branched alkyl group. Examples of alkyls include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, 1-pentyl, 2-pentyl, 3-pentyl, neopentyl, 1 -hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1-octyl, 2-octyl, 3-octyl and 4-octyl. The alkyl group may be optionally substituted.

As used herein, the term haloalkyl refers to an alkyl substituted with one or more halogen atoms, where the halogen and alkyl group are as defined above. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, chloromethyl, trifluoromethyl and 2,2,2-trifluoroethyl.

As used herein, the term hydroxyalkyl or hydroxyalkyl refers to an alkyl group, as defined above, where one or more hydrogen atoms in the alkyl group are replaced by hydroxyl groups. Examples of hydroxyalkyl moieties include, but are not limited to

- 40 046626 indicated, -CH2OH, -CH2CH2OH, CH2CH2CH2OH, -CHSNSCCHSNON, -CH2SCCHCHSN3, -CH(CH3)CH2OH.

As used herein, heterocycloalkyl refers to a non-aromatic, saturated or partially saturated, bridged bicyclic, spirocyclic, monocyclic or polycyclic ring system containing from 3 to 15 members containing at least one heteroatom or heterogroup selected from O, N, S, S(O), S(O) ₂ , NH and C(O), the remaining atoms in the ring being independently selected from the group consisting of carbon, oxygen, nitrogen and sulfur. The term heterocycloalkyl also refers to a bridged bicyclic ring system containing at least one heteroatom or heterogroup selected from O, N, S, S(O), S(O) ₂ , NH and and C(O). Examples of heterocycloalkyls include, but are not limited to, azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, dihydropyridinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl, oxidothiomorpholinyl, oxapiperazinyl, oxapiperidinyl, tetrahydrofuryl , tetrahydropyranyl, tetrahydrothiophenyl, dihydropyranyl, indolinyl, indolinylmethyl, isoindolinyl, oxoisoindolinyl, dioxoisoindolinyl, aza-bicyclooctanyl, diazabicyclooctanyl, azocinyl, chromanyl, isochromanyl, xanthenyl, 2oxa-6-azaspiro[3.3]heptanyl. The heterocycloalkyl substituent can be attached either through a carbon atom or through a heteroatom. The heterocycloalkyl group may be optionally substituted with one or more suitable groups according to one or more of the above groups. Preferably, heterocycloalkyl refers to a 5-6 membered ring selected from the group consisting of azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl and thiomorpholinyl. All heterocycloalkyls are optionally substituted with one or more of the above groups.

As used herein, the term heteroaryl, alone or in combination with other term(s), refers to a completely unsaturated ring system containing only 5 to 14 ring atoms. At least one of the atoms in the ring is a heteroatom (ie, oxygen, nitrogen, or sulfur), with the remaining atoms/groups in the ring independently selected from carbon, oxygen, nitrogen, or sulfur. Heteroaryl may contain one ring (monocyclic) or multiple rings (bicyclic, tricyclic or polycyclic) fused together or linked by a covalent bond. Preferably, the heteroaryl is a 5-6 membered ring. The rings may contain from 1 to 4 additional heteroatoms selected from N, O and S, where the N atom is optionally quaternary. The heteroaryl moiety can be attached by a covalent bond at any suitable position on the ring with a given chemical structure. Examples of heteroaryls include, but are not limited to, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, cinnolinyl, isoxazolyl, thiazolyl, isothiazolyl, N-tetrazolyl, oxadiazolyl, triazolyl, pyridyl, 3-fluoropyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzoxazolyl , benzisoxazolyl; benzothiazolyl, benzofuranyl, benzothienyl, benzotriazinyl, phthalazinyl, tianthrene, dibenzofuranyl, dibenzothienyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, purinyl, pteridinyl, 9H-carbazolyl, α-carbolinyl, , benzisothiazolyl, benzoxazolyl, pyrrolopyridyl, furopyridinyl, purinyl, benzothiadiazolyl, benzooxadiazolyl, benzotriazolyl, benzotriadiazolyl, carbazolyl, dibenzothienyl, acridinyl, etc. The heteroaryl group may optionally be further substituted.

As used herein, the term alkenyl refers to a carbon chain that contains at least one carbon-carbon double bond and which may be linear or branched or contain combinations of these chains. Examples of alkenyls include, but are not limited to, vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl and 2-methyl-2-butenyl.

As used herein, the term amino refers to the -NH2 group.

As used herein, the term halogen or halogen, alone or in combination with other term(s), refers to fluorine, chlorine, bromine or iodine.

As used herein, the term hydroxy or hydroxyl, alone or in combination with other term(s), means -OH.

As used herein, the term oxo refers to the =O group.

As used herein, the term alkoxy refers to an -O-alkyl group, where the alkyl group is as defined above. Examples of C ₁ -C ₁₀ alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, n-butoxy or t-butoxy. The alkoxy group may optionally be substituted with one or more suitable groups.

As used herein, the term aryl represents an optionally substituted monocyclic, bicyclic or polycyclic aromatic hydrocarbon ring system containing from about 6 to 14 carbon atoms. Examples of C ₆ -C1 ₄ aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl, anthryl, fluorenyl, indanyl, biphenylethyl and acenaphthyl. The aryl group may be unsubstituted or substituted by one or more suitable groups.

- 41 046626

The term acyl refers to the group R-CO- or -CO-R, where R represents an optionally substituted alkyl group as defined above. Examples of acyl groups include, but are not limited _to , CH3CO- _, CH3CH2CO-, _CH3CH2CH2CO- or (CH3) _2CHCO- . The term -O-acyl refers to -O-CO-R, where R is alkyl, as defined above.

The term heteroatom as used herein means a sulfur, nitrogen or oxygen atom.

The term subject means a mammal, such as a human. In one embodiment, the subject refers to any subject suffering from prostate disease. In another embodiment, the term subject refers to any subject suffering from prostate cancer. In another embodiment, the term subject refers to any subject suffering from castration-resistant prostate cancer. In another embodiment, the term subject refers to any subject who has been castrated. In another embodiment, the term subject refers to any subject who has received antiandrogen therapy. In another embodiment, the term subject refers to any subject suffering from castration-resistant prostate cancer receiving a SMARCA2/4 disrupting agent as first-line therapy. In another embodiment, the term subject refers to any subject suffering from castration-resistant prostate cancer receiving combination therapy comprising a SMARCA2/4 disrupting agent and any other therapeutic agents.

The term "moderate responder" to treatment with a SMARCA2/4 disrupting agent, when describing a subject according to the present invention, means a subject who has any one of the tumor-specific changes according to the present invention.

The term “high responder” to treatment with a SMARCA2/4 disrupting agent, when describing a subject according to the present invention, means a subject who has at least two tumor-specific changes according to the present invention. For example, a subject may be described as having a high response rate to treatment with a SMARCA2/4 disrupting agent if the following changes occur:

i. mutation, amplification or increased expression of the androgen receptor (AR) gene; and loss-of-function mutation or deleterious mutation in phosphatase and tensin homolog (PTEN);

ii. loss-of-function mutation or deleterious phosphatase and tensin homolog (PTEN) mutation and genomic rearrangement that results in translocation of the TMPRSS2 and ERG genes;

and iii. mutation, amplification or increased expression of the androgen receptor (AR) gene; and a genomic rearrangement that leads to translocation of the TMPRSS2 and ERG genes.

experimental part

Synthetic methods for preparing the compounds of the present invention are described in international patent application PCT/IB2019/053443, the contents of which are incorporated herein in their entirety.

Example-1:

Determination of antiproliferative activity of a SMARCA2/4 disrupting agent in cells in the Cell Titer Glo® (Promega) study:

Prostate cancer cell lines were seeded, Vcap (ATCC, cat. no. CRL-2876), LNCaPFGC (ATCC CRL-1740), 22RV1 (ATCC CRL-2505), PC-3 (ATCC CRL-1435), DU-145 (ATCC HTB-81) and RWPE-1 (ATCC CRL-11609) into a 96-well black clear flat bottom plate (Corning, cat. #3904) using appropriate complete media. At the same time, cells were plated for measurements on day 0.

The next day, compound 43 of the present invention was added to the cells from 10 mM stock solutions prepared in DMSO (Sigma, cat. no. D2650). DMSO alone was used as vehicle control. The reaction in the measurement plate was terminated on day 0 by adding 50 μl of Cell Titer Glo® reagent (Promega, KaT. No. G7572) on the day of addition of the compound. The compound was incubated for 8 days with the exception of 22RV1 cells, for which incubation was carried out for 6 days. On day 4, the medium was replenished with fresh compound. After incubation, the compounds were terminated using 50 μl of CellTiter Glo® reagent. The CellTiter Glo® luminescent reagent allows the determination of the number of viable cells based on the quantification of ATP present, which is an indicator of cell number and metabolic activity. Luminescence data were recorded on a fluorescence plate reader.

The CTG results at day 0 are designated as time zero (Tz), the final CTG measurement in the vehicle control group is designated as growth control, DMSO (C), and the results in the growth study in the presence of nine drug concentrations are designated as (Ti).

Using the results of the measurements [zero time (Tz), growth control, DMSO (C), and results in the growth study in the presence of nine drug concentrations (Ti)] were calculated

-

Claims (6)

percentage increase value for each drug concentration. The percentage response rate was calculated as: [(Ti-Tz)/(C-Tz)] x 100, for concentrations at which Ti > Tz f(Ti-Tz)/Tz] x 100, for concentrations at which Ti<Tz Three dose-response parameters were calculated for each experimental agent. A 50% growth inhibition (GI50), which was calculated using the equation [(Ti-Tz)/(C-Tz)]x100=50, corresponds to a drug concentration that produces a 50% reduction in the total increase in luminescence signal (measured ATP level ) compared to control cells after incubation with the drug. The results are shown in the table. LC50 (the concentration that produces a 50% reduction in the measured ATP level after completion of drug treatment compared to that at the beginning of treatment), which indicates the overall decrease in cell number after treatment, is calculated using the equation [(Ti-Tz)/Tz] x 100=-50. Determination of susceptibility of prostate cancer cell lines to a SMARCA2/4 disrupting agent. Compound 43 of the present invention was analyzed against several cell lines corresponding to normal and prostate cancer cells. The cell lines used in the present invention have one or more tumor-specific changes, such as the presence of AR, PTEN mutations or TMPRSS2-ERG fusion, which are presented below. Cell line GI ₅ o (nM) Observed cell killing Tumor-specific changes according to the present invention AR addiction PTEN mutation Merge TMPRSS2ERG RWPE (normal) 260* No Normal AR level - - DU145 >10000 No - - - 22RV1 14 No + - - RSZ 51 Yes (LC ₅₀ = 3406 nM) - + - VCap 3 Yes (LC50 =11 nm) + - + LnCapFGC 5 Yes (LC ₅₀ = 22 nM) + + - The '+' sign indicates the presence of a particular tumor-specific change in the corresponding cell line. The '' sign indicates the absence of a particular tumor-specific change in the corresponding cell line. It was found that in normal cells (RWPE), the compound did not show any inhibition or cell killing (Figure 1). The DU145 prostate cancer cell line lacks tumor-specific changes and has shown neither cell growth inhibition nor cell killing, and thus DU145 has been determined to have no or poor response to a SMARCA2/4 disrupting agent (Fig. 2). The growth of 22RV1 and PC3, cell lines having one of these tumor-specific changes, was suppressed to a significant extent, while the cells were not killed or killed in moderate numbers (Fig. 3A and 3B). There were significant effects on both growth and cell killing in the VCap and LnCapFGC cell lines, which had two of the three tumor-specific changes indicated (Fig. 4A and 4B). These observations support the use of AR dependence, PTEN mutation, and the presence of the TMPRSS2-ERG gene fusion as biomarkers to determine the susceptibility of prostate cancer cell lines to SMARCA2/4-disrupting agents. CLAIM 1. A method of treating prostate cancer in a subject in need thereof, comprising: a) determining whether the subject has responded to treatment with at least one SMARCA2/4 disrupting agent, comprising the steps of: i. isolating a biological sample from the subject; ii. determining the presence of tumor-specific changes, where the specified tumor-specific change is: mutation, amplification or increased expression of the androgen receptor (AR) gene; loss-of-function mutation or deleterious mutation in phosphatase and tensin homologue (PTEN); or a genomic rearrangement that leads to translocation of the TMPRSS2 gene and the ERG gene; iii. to determine whether a subject has responded to a specified treatment if there is at least one - 43 046626 from tumor-specific changes; And b) administering a therapeutically effective amount of at least one SMARCA2/4 disrupting agent to a subject who has responded to treatment; wherein said SMARCA2/4 disrupting agent is a compound of formula (I): or a pharmaceutically acceptable salt or stereoisomer thereof; where R1 represents hydrogen, halogen, hydroxy(C ₁ -C ₆ )alkyl, -COORa, -CON(Ra) ₂ or phenyl; wherein the phenyl is optionally independently substituted with at least one of hydroxy, (C1- _C6 )alkoxy, halogen, ( _C1 - _C6 )alkyl, amino, -ONa, -COORa or -OCORa; wherein Ra in each case represents hydrogen or (C1-C ₆ )alkyl; R2 is -NH2 or -OH; ring A is a 4-8 membered heterocycloalkyl ring or a 5-6 membered heteroaryl ring, each containing 1-2 N heteroatoms, each optionally independently substituted with at least one hydroxy; L is a linker with the chemical structure: wherein the left side of the linker is attached to ring A, and the right side of the linker is attached to the targeting ligand (TL); R _b represents hydrogen; R _c represents (C1-C ₆ )alkyl; n is from 0 to 10, and p is from 1 to 5; the targeting ligand (TL) is: wherein R6 is hydrogen, (C1- _C6 )alkyl or halo(C1- _C2 )alkyl; R7 is -O-R5 or halogen; wherein R5 represents hydrogen, (C1- _C6 )alkyl, (CrO^acyl or Na; and R ₈ represents hydrogen or (C1- _C4 )alkyl, providing results in the treatment of prostate cancer. 2. The method of claim 1, wherein the sensitivity of prostate cancer cells to SMARCA2/4 disrupting agents in a subject who has responded to treatment with one tumor-specific change is less than the sensitivity of prostate cancer cells in the subject , who showed a strong response to treatment with SMARCA2/4-disrupting agents, with at least two tumor-specific changes. - 44 046626 3. The method according to claim 1, characterized in that said SMARCA2/4 degrading agent is a compound represented by the formula (IA), (IB), (IC) or (ID): or a pharmaceutically acceptable salt or stereoisomer thereof. 4. The method according to claim 1, characterized in that said subject has undergone castration or antiandrogen therapy. 5. The method according to claim 1, characterized in that the prostate cancer is castration-resistant prostate cancer. 6. Method according to any one of claims 1 to 5, characterized in that said SMARCA2/4 degrading agent is a compound with the chemical structure: Connection no. Structure - 45 046626 - 46 046626 - 47 046626 - 48 046626 - 49 046626 - 50 046626 - 51 046626 - 52 046626 - 53 046626 - 54 046626 - 55 046626 - 56 046626 - 57 046626 - 58 046626 - 59 046626 - 60 046626 - 61 046626 - 62 046626 - 63 046626 - 64 046626 - 65 046626 - 66 046626 or a pharmaceutically acceptable salt or stereoisomer thereof. -