RNA binding motion protein 39 (RBM39) degradation agents for the treatment of

Abstract

There is provided a method for treating a homologous recombination (HR) deficient cancer, a homologous recombination (HR) function normal cancer, or a cancer that is resistant to DNA repair and DNA damage response (DDR) inhibitor therapy, such as poly (ADP-ribose) polymerase (PARP) inhibitor therapy, comprising administering to a subject an RNA binding motif protein 39 (RBM39) degrading agent, such as an arylsulfonamide. A DDR inhibitor, such as a PARP inhibitor, may also be administered. Also provided are compositions comprising an RBM39 degrading agent (such as an arylsulfonamide, e.g., E7820 or Compound A) and a DDR inhibitor (such as a PARP inhibitor).

Description

Technical Field

[0001] The present disclosure provides a method for treating (i) homologous recombination (HR)-deficient cancers, (ii) homologous recombination (HR)-normal cancers, and (iii) cancers resistant to DNA repair and DNA damage response (DDR) inhibitor therapy using an RNA binding motif protein 39 (RBM39) degrader. The RBM39 degrader can be combined with a DDR inhibitor (such as a poly (ADP-ribose) polymerase (PARP) inhibitor), and the present disclosure further relates to a composition comprising an RBM39 degrader and a DDR inhibitor (such as a PARP inhibitor). Background Art

[0002] DNA repair and DNA damage response (DDR) are often disrupted in many cancers and are considered hallmarks of cancer. Cancer cells with defects in the DDR pathway accumulate genomic instability, which exacerbates their aggressive behavior. However, tumors can survive by relying on alternative repair pathways to compensate for these defects. This provides an opportunity for targeted therapeutics that can be designed to selectively inhibit these alternative repair pathways and induce synthetic lethality (Brown, JS et al. Cancer Discov. [Cancer Discovery], 2017, 7(1): 20-37).

[0003] Several large-scale genomic datasets have highlighted that many cancers, such as ovarian, breast, prostate, pancreatic, non-small cell lung cancer, and small cell lung cancer, harbor molecular alterations within the DDR repair network (Knijnenburg TA et al. Cell Rep. 2018, 23(1):239–254. Sen T. et al. Transl Lung Cancer Res. 2018, 7(1):50-68). Although patients with genetic abnormalities in the DDR pathway, such as homologous recombination (HR), can be treated with DDR inhibitors, such as poly (ADP-ribose) polymerase (PARP) inhibitors, many cancers eventually develop resistance (Brown, JS et al. Cancer Discov. 2017, 7(1):20-37). In addition, a large proportion of patients fail to derive significant benefit from DDR / PARP inhibition due to the lack of DDR gene defects. These patients are often referred to as homologous recombination deficiency-negative (HRD-negative), homologous recombination proficient (HRP), or homologous recombination repair-negative (HRR-negative) and have a poor prognosis and limited treatment options. Therefore, there is a need to develop therapeutic agents that can modulate DNA repair mechanisms to treat HRD-negative, HRP-negative, or HRR-negative cancers, as well as cancers that are resistant to DDR / PARP inhibitors.

[0004] Cyclin-dependent kinases (CDKs) are a group of serine / threonine protein kinases that play a key role in various biological processes by regulating the cell cycle and gene transcription. Recent reports have identified cyclin-dependent kinase 12 (CDK12) as a transcription-related CDK that forms a complex with cyclin K (CCNK) and phosphorylates RNA polymerase II (RNAP2) to initiate transcriptional elongation of several genes related to DNA damage response, cell cycle control, RNA splicing, and genomic stability maintenance (Dubbury, S. et al. Nature. [Nature], 2018, 564, 141-145. Liang S et al. Cells. [Cell], 20209 (6): 1483).

[0005] Several reports have shown that genetic or pharmacological depletion of CDK12 can reduce the expression of several genes involved in the homologous recombination repair pathway (such as BRCA1 and BRCA2), thereby inducing a BRCAness-like phenotype that may lead to a synthetic lethal phenotype when combined with DDR inhibitors (such as PARP inhibitors). Preclinical studies have demonstrated this synergistic combination in cancer cell line-derived and patient-derived mouse models. In addition, genome-wide studies have shown that CDK12 deficiency may predict clinical sensitivity to DDR / PARP inhibitors. Therefore, CDK12 has received widespread attention as a therapeutic target and tumor biomarker for patients who develop resistance to DDR / PARP inhibitors or in combination with DDR / PARP inhibitors for HRD-negative tumors (Bajrami I. et al. Cancer Res. [Cancer Research], 2014, 74(1):287-97. Johnson SF et al. Cell Rep. [Cell Reports], 2016 Nov 22; 17(9):2367-2381).

[0006] It is reported that CDK12 also shares a largely conserved kinase domain with CDK13, whose biological role is not yet fully understood. Gene depletion studies have shown that although CDK12 and CDK13 are not completely redundant, dual inhibition of the two is the cause of significant global transcriptional changes, which are induced by the fact that these kinases increase the processivity of RNA polymerase II relative to either kinase alone. Given that CDK12 inhibition primarily affects DNA damage response gene expression, selective targeting of CDK12 or CDK13 (in combination with PARP inhibitors) may reduce unnecessary side effects associated with global RNA polymerase II disruption (Fan, Z. et al. Sci Adv. [Science Advances], 2020, 6 (18): eaaz5041. Krajewska, M. et al. Nat Commu. [Nature Communications], 2019, 10: 1757). Therefore, the development of pharmacologically selective CDK12 inhibitors is a major challenge because CDK12 and CDK13 share highly similar sequences.

[0007] Arylsulfonamides act as molecular glue degraders of RNA-binding motif protein 39 (RBM39) by forming a ternary complex with RBM39 and the E3 ubiquitin ligase receptor DDB1 and CUL4-associated factor 15 (DCAF15), without having detectable affinity for either species alone. These molecular glues promote the interaction of the RBM39 splicing factor and the CUL4-DCAF15 E3 ubiquitin ligase, leading to polyubiquitination and proteasomal degradation of RBM39. In human cancer cell lines treated with arylsulfonamides, degradation of RBM39 leads to significant antiproliferative effects. In addition, silencing DCAF15 in cancer cells using CRISPR-Cas9 can resist degradation of RBM39 by arylsulfonamide compounds, highlighting that RBM39 degradation is the main mechanism by which these compounds exert their anti-cancer effects (Han et al., Science. [Science], 2017, 356(6336). Du et al. Structure. [Structure], 2019, 1625-1633). In addition, gene knockout experiments of RBM39-deficient human cancer cells injected into mice slowed the progression of leukemia and improved overall survival (Wang et al. Cancer Cell. [Cancer Cell], 2019, 35(3): 369-384).

[0008] It has been previously demonstrated that arylsulfonamide compounds exhibit acceptable safety profiles in clinical trials and have shown some anti-tumor efficacy in a variety of cancers. Therefore, RBM39 degraders are expected to become effective treatments for specific types of human cancers, which deserves further exploration (Wang et al. Cancer Cell. [Cancer Cell], 2019, 35(3): 369-384). However, the overall response rate remains low, which may be due to a lack of understanding of its mechanism of action and potential response biomarkers. Summary of the Invention

[0009] Aspects of the present disclosure relate, in part, to the surprising discovery that a similar functional relationship exists specifically for (i) RNA binding motif protein 39 (RBM39) and (ii) cyclin-dependent kinase 12 (CDK12) in the transcriptional regulation of the homologous recombination (HR) repair machinery and cell cycle checkpoint control. Thus, RBM39 degraders can be used to treat cancers for which CDK12 is a suitable therapeutic target, e.g., cancers in which patients develop resistance to DDR / PARP inhibitors or cancers in which patients are HRD-negative / HR-normal tumors. Advantageously, the inventors have demonstrated that RBM39 degradation can phenotypically mimic CDK12 inhibition while minimizing effects on other cyclin-dependent kinases, thereby reducing unwanted side effects associated with global RNA polymerase II disruption.

[0010] Accordingly, a first aspect of the present disclosure provides a method for treating a homologous recombination (HR)-deficient cancer in a subject in need thereof, the method comprising administering to the subject an RNA-binding motif protein 39 (RBM39) degrader in an amount effective to treat the HR-deficient cancer.

[0011] Accordingly, the present disclosure provides an RBM39 degrader for use in treating homologous recombination (HR)-deficient cancer in a subject in need thereof.

[0012] The method can further comprise administering to the subject a DNA repair and DNA damage response (DDR) inhibitor in an amount effective to treat the cancer.

[0013] A second aspect of the present disclosure provides a method for treating homologous recombination (HR)-normal cancer in a subject in need thereof, the method comprising administering to the subject an RNA-binding motif protein 39 (RBM39) degrader in an amount effective to treat the HR-normal cancer.

[0014] Thus, the present disclosure provides an RBM39 degrader for use in treating homologous recombination (HR)-normal cancer in a subject in need thereof.

[0015] The method can further comprise administering to the subject a DNA repair and DNA damage response (DDR) inhibitor in an amount effective to treat the cancer.

[0016] According to a third aspect of the present disclosure, there is provided a method for treating a cancer that is resistant to DNA repair and DNA damage response (DDR) inhibitor therapy, such as poly (ADP-ribose) polymerase (PARP) inhibitor therapy, in a subject in need thereof, the method comprising administering to the subject an RNA binding motif protein 39 (RBM39) degrader in an amount effective to treat the cancer that is resistant to the DDR inhibitor therapy.

[0017] Therefore, the present disclosure also provides an RBM39 degrader for use in treating cancer resistant to DDR inhibitor therapy (such as PARP inhibitor therapy) in a subject in need thereof.

[0018] The method can further comprise administering to the subject a DNA repair and DNA damage response (DDR) inhibitor in an amount effective to treat the cancer.

[0019] According to a fourth aspect of the present disclosure, there is provided a composition comprising an RNA binding motif protein 39 (RBM39) degrader and a DNA repair and DNA damage response (DDR) inhibitor, such as a poly (ADP-ribose) polymerase (PARP) inhibitor.

[0020] According to a fifth aspect of the present disclosure, there is provided a method for predicting the response of a cancer subject to treatment with an RNA binding motif protein 39 (RBM39) degrader, the method comprising determining the subject's response to treatment with a DNA repair and DNA damage response (DDR) inhibitor therapy (such as poly (ADP-ribose) polymerase (PARP) inhibitor therapy), wherein a subject resistant to DDR inhibitor therapy may benefit from treatment with an RBM39 degrader. The method may include administering an RBM39 degrader to the subject in an amount effective to treat the cancer, wherein the subject is identified as resistant to DDR inhibitor therapy. The method may further comprise administering a DNA repair and DNA damage response (DDR) inhibitor to the subject in an amount effective to treat the cancer.

[0021] According to a sixth aspect of the present disclosure, there is provided a method for predicting the response of a cancer subject to treatment with an RNA binding motif protein 39 (RBM39) degrader, the method comprising determining the homologous recombination deficiency (HRD) status of the subject. The method may comprise administering an RBM39 degrader to the subject. The method may further comprise administering a DNA repair and DNA damage response (DDR) inhibitor to the subject in an amount effective to treat the cancer. In particular, the method may comprise administering an RBM39 degrader to the subject in an amount effective to treat the cancer, wherein the subject is identified as HR-deficient. The RBM39 degrader may be administered as a single agent or in combination with a DDR inhibitor, wherein the subject is identified as HR-deficient. The method may comprise administering both an RBM39 degrader and a DDR inhibitor to the subject, wherein the subject is identified as having normal HR function. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] The present disclosure will be more clearly understood from the following description of some embodiments of the present disclosure (given by way of example only) with reference to the following drawings:

[0023] Figure 1A Results show tumor volume in the HRD-negative OVCAR3 CDX model treated with the RBM39 degrader E7820 alone or in combination with olaparib. Figure 1B Tumor growth inhibition (TGI) of the treatment was demonstrated;

[0024] Figure 2A -H shows the pharmacodynamic markers of tumor samples harvested from the in vivo CDX study of Example 1, Figure 2A for BRCA1; Figure 2B for MCL1; Figure 2C is pHH3; Figure 2D for RBM39; Figure 2E for CDK12; Figure 2F for CDK7; Figure 2G for CDK9; Figure 2H CDK1 / 2 / 3 / 5;

[0025] Figure 3A Figure 3 shows tumor volume in the BRCA-normal PARP-resistant OV0273 PDX model treated with E7820 alone or in combination with olaparib. Figure 3B Tumor growth inhibition (TGI) results of the treatment were presented;

[0026] Figure 4A A single spider graph shows mice treated with E7820 monotherapy in the BRCA 1 / 2-normal and PARP-resistant OV0273 PDX model. Figure 4B Shown are individual spider images of mice treated with the E7820+olaparib combination in this model;

[0027] Figure 5 Shows overall survival results for E7820 monotherapy or in combination with olaparib in the BRCA1 / 2-normal, PARP-resistant OV0273 PDX model;

[0028] Figure 6 Shows the number of complete regressions observed with E7820 alone and in combination with olaparib in the BRCA1 / 2-normal, PARP-resistant OV0273 PDX model;

[0029] Figure 7A Figure 2 shows tumor volumes in the BRCA-normal OV90 CDX model treated with niraparib, olaparib, the combination of E7820 and niraparib, and the combination of E7820 and olaparib. Figure 7B Tumor Growth Index (TGI) results for this treatment are presented;

[0030] Figure 8A and 8B demonstrated the use of CDK12 / 13 inhibitors THZ531 and SR-4835 ( Figure 8A ) or the RBM39 degrader E7820 and indisulam ( Figure 8B ) Viability curve of HRD-negative human ovarian cancer cell line OVCAR3 treated for 72 hours;

[0031] Figure 9 shows the CDK12 kinase activity curves of the human epithelial kidney cell line HEK293 treated for 1 hour with the CDK12 / 13 inhibitor THZ531, the CDK12 degrader CR8, the RBM39 degraders E7820 and indifamide, and the pan-CDK inhibitor AT7519; and

[0032] Figure 10A and Figure 10B Shown was treated with E7820 for 6 hours ( Figure 10A ) and 24 hours ( Figure 10B BRCA1 and ATR ( Figure 10A ) and additional DNA repair and cell cycle genes ( Figure 10B ) gene expression changes.

[0033] FIG11 shows the tumor volume results of OV0273PDX mouse model with normal BRCA 1 / 2 function and resistance to PARP treated with Compound A alone or in combination with niraparib ( Figure 11A ), tumor growth inhibition results ( Figure 11B ) and target engagement markers from tumor samples ( Figure 11C ). DETAILED DESCRIPTION

[0034] As disclosed herein, many small molecules have been studied for HRD-deficient cancers that are resistant to PARP inhibitors, and E7820 has been shown to be effective alone or in combination with PARP inhibitors in preclinical mouse cancer models. In order to select E7820 as a potential therapeutic agent for this disease, a high-content phenotypic whole-genome array CRISPR / Cas9 screening was developed in HUVEC cells to identify the cellular and structural changes associated with gene knockout of human genes. The high-dimensional biological dataset of the single gene knockout phenotype was then compared with the cellular and structural changes produced by more than 200,000 small molecule treatments in intron-controlled wild-type HUVEC cells. Using machine vision and automated analysis software, hundreds of cellular parameters associated with CDK12 knockout were quantified to elucidate therapeutic compounds that may phenotype mimic CDK12 loss, thereby identifying a number of arylsulfonamide compounds (indisulfonamide, tasisulam, CQS, and E7820). Using the same approach, we further demonstrated that all of these arylsulfonamides also phenotypically mimic RNA-binding motif protein 39 (RBM39) CRISPR / Cas9 knockout, validating the recently discovered mechanism by which these compounds act as molecular glue degraders of RBM39 by forming a ternary complex with RBM39 and the E3 ubiquitin ligase receptor DDB1 and CUL4-associated factor 15 (DCAF15). Therefore, RBM39 degraders such as these arylsulfonamides could be used to treat cancers for which CDK12 is a suitable therapeutic target, such as cancers in which patients develop resistance to PARP inhibitors or cancers with HRD-negative / HR-normal tumors. Similar to CDK12 depletion, when combined with DDR inhibitors such as PARP inhibitors, RBM39 degraders could be used to induce a synthetic lethal phenotype, enabling the treatment of patients who would not benefit from treatment with DDR inhibitors in the absence of RBM39 degraders. Homologous recombination deficiency (HRD) status

[0035] Homologous recombination deficiency (HRD) is a tumor feature, which is defined as the double-strand breaks (DSBs) in DNA that cannot be accurately repaired via homologous recombination (HR). HRD status can be assessed via assessment of genomic instability. In particular, HRD status can be scored by measuring the system of the genomic defects reflecting HR defects, which include quantifying loss of heterozygosity (LOH), telomeric allele imbalance and large-scale state transitions. The deleterious mutation of some genes (such as breast cancer susceptibility genes 1 or 2 (BRCA1 and / or BRCA2), the gene related to Fanconi anemia repair pathway, ATM, TP53, the gene related to base excision repair pathway, the gene related to non-homologous end joining pathway, the gene related to alternative end joining pathway) is relevant to the HR defects in some cancers. Therefore, HRD status can also be assessed based on the presence or absence of one or more deleterious mutations in one or more genes associated with HR defects (e.g., BRCA1 and / or BRCA2 genes, genes associated with the Fanconi anemia repair pathway, ATM, TP53, genes associated with the base excision repair pathway, genes associated with the non-homologous end joining pathway, and genes associated with the alternative end joining pathway. In particular, HRD status can be assessed based on the presence or absence of a single deleterious mutation in the BRCA1 and / or BRCA2 genes.

[0036] For example, for ovarian cancer, HRD status can be determined by two biomarkers: (i) germline mutations in the BRCA1 and / or BRCA2 genes that result in deleterious or benign mutations, or (ii) the level of genomic instability as assessed by loss of heterozygosity, telomeric allelic imbalance, and large-scale state transitions, where the sum of these three independent measures quantifies a positive or negative state outcome. For prostate cancer, HRD status can be determined by germline or somatic mutations in the HRR pathway: BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and / or RAD54L. For breast and pancreatic cancer, HRD status can be determined by deleterious germline BRCA1 / 2 mutations, where all patients who are BRCA1 / 2 positive are also HRD positive. However, a patient can be BRCA 1 / 2 negative but still HRD positive, as is the case with ovarian cancer when referring to HRD status using the second definition above. Genetic tests are available for clinicians to determine HRD status for clinical use of PARP inhibitors (e.g., Myraid, Foundation Medicine, Caris, and Tempus). For Myraid's CDx test, HRD positivity is defined as the presence of a tBRCA mutation and / or a tBRCA mutation identified by Myraid. CDx HRD scores ≥ 42, as these scores are at the 95th percentile of HRD scores observed in patients with BRCA 1 / 2 deficiency. HRD-negative was defined as the absence of tBRCA mutations and / or CDx HRD score <42. Unknown HRD is defined as test failure, indeterminate, or missing results (https: / / www.accessdata.fda.gov / cdrh_docs / pdf19 / P190014B.pdf). For Foundation Medicine's CDx test, HRD-positive is defined as the presence of a tBRCA mutation and / or LOH score >16% (https: / / www.accessdata.fda.gov / cdrh_docs / pdf16 / p160018S001c.pdf).

[0037] The terms "HRD positive" and "HR defective" are used interchangeably herein and refer to cancers / tumors with one or more markers of genomic instability, such as one or more deleterious mutations in genes associated with HR defects (e.g., BRCA1 / 2) and positive genomic instability (GIS). The terms "HRD negative," "HR function normal," and "homologous recombination repair negative (HRR negative)" are used interchangeably herein and refer to cancers / tumors lacking DDR gene defects, i.e., cancers / tumors lacking genomic instability, such as deleterious mutations in genes associated with HR defects (e.g., BRCA1 / 2). As used herein, the term "BRCA 1 / 2 function normal" refers to cancers in which a subject has functional BRCA 1 and 2 proteins (which induce genomic stability). The genes associated with HR defects can be selected from the group consisting of: BRCA genes, genes associated with the Fanconi anemia repair pathway, ATM, TP53, genes associated with the base excision repair pathway, genes associated with the non-homologous end joining pathway, and genes associated with the alternative end joining pathway. The one or more mutations are mutations in the cells and / or tumors of the cancer. The one or more mutations may be somatic mutations and / or germline mutations. The one or more mutations may result in loss of function of the gene in question.

[0038] Therefore, the method as disclosed herein may include a step of determining the homologous recombination deficiency (HRD) status of the subject. For example, the method may include a step of quantifying loss of heterozygosity (LOH), telomeric allele imbalance and / or large-scale state transitions. Additionally or alternatively, the method may include a step of determining whether one or more harmful mutations are present in one or more genes associated with HR defects (such as breast cancer susceptibility genes 1 or 2 (BRCA1 or BRCA2), genes associated with Fanconi anemia repair pathways, ATM, TP53, genes associated with base excision repair pathways, genes associated with non-homologous end joining pathways, and genes associated with alternative end joining pathways). In particular, the method may include a step of determining whether one or more harmful mutations are present in breast cancer susceptibility genes 1 and / or 2 (BRCA1 and / or BRCA2). DNA repair and DNA damage response (DDR) inhibitors

[0039] DNA repair and DNA damage response (DDR) inhibitors, such as poly (ADP-ribose) polymerase (PARP) inhibitors, may also be administered to the subject. Thus, the disclosed methods may include the step of administering to the subject a DDR inhibitor, such as a PARP inhibitor.

[0040] As used herein, the term "DDR inhibitor" refers to any compound that inhibits, blocks or reduces DNA repair and DNA damage response. In cancer treatment, blocking DNA repair and DNA damage response may help prevent cancer cells from repairing their damaged DNA, thereby causing them to die. The DDR inhibitor can be a poly (ADP-ribose) polymerase (PARP) inhibitor. The DDR inhibitor can be an ATR inhibitor. The DDR inhibitor can be a CHK1 inhibitor. The DDR inhibitor can be selected from the group consisting of: inhibitors of WEE, RAD51, ATR, PolTheta, BLM, WRN, PARG, USP1 and DNAPKc.

[0041] As used herein, the term "DDR inhibitor" is understood to encompass pharmaceutically acceptable salts thereof. As used herein, the term "DDR inhibitor" may refer to one DDR inhibitor or a combination of two or more DDR inhibitors.

[0042] When combined with DDR inhibitors, RBM39 degraders can induce a synthetic lethal phenotype, enabling treatment of patients who would not benefit from treatment with DDR inhibitors in the absence of the RBM39 degrader. Poly (ADP-ribose) polymerase (PARP) inhibitors

[0043] Poly (ADP-ribose) polymerase (PARP) helps repair damaged DNA. As used herein, the term "PARP inhibitor" refers to any compound that inhibits or blocks PARP, i.e., any compound that downregulates, reduces, or stops the expression, activity, and / or function of PARP. In cancer treatment, blocking PARP may help prevent cancer cells from repairing their damaged DNA, thereby causing their death.

[0044] The PARP inhibitor may be selected from the group consisting of: olaparib, niraparib, talazoparib, and rucaparib. The PARP inhibitor may be olaparib. The PARP inhibitor may be niraparib.

[0045] As used herein, the term "PARP inhibitor" is understood to encompass pharmaceutically acceptable salts thereof. As used herein, the term "PARP inhibitor" may refer to one PARP inhibitor or a combination of two or more PARP inhibitors. cancer

[0046] The cancer may be selected from the group consisting of ovarian cancer, breast cancer, prostate cancer, gastric cancer, pancreatic cancer, KRAS mutant cancer, acute myeloid leukemia, colon cancer, neuroblastoma, hematopoietic cancer, lymphoid cancer, non-small cell lung cancer and small cell lung cancer. The cancer may be ovarian cancer.

[0047] The cancer may be a HR normal cancer. The HR normal cancer may be selected from the group consisting of ovarian cancer, breast cancer, prostate cancer, gastric cancer, pancreatic cancer, non-small cell lung cancer, and small cell lung cancer. The HR normal cancer may be ovarian cancer.

[0048] The cancer may be BRCA 1 / 2 normal. The BRCA 1 / 2 normal cancer may be selected from the group consisting of ovarian cancer, breast cancer, prostate cancer, gastric cancer, pancreatic cancer, non-small cell lung cancer, and small cell lung cancer. The BRCA 1 / 2 normal cancer may be ovarian cancer.

[0049] The cancer may be an HR-deficient cancer. In particular, the cancer may be an HR-deficient cancer that is resistant to treatment with a DDR inhibitor (such as a PARP inhibitor). The HR-deficient cancer may be selected from the group consisting of ovarian cancer, breast cancer, prostate cancer, gastric cancer, pancreatic cancer, non-small cell lung cancer, and small cell lung cancer. The HR-deficient cancer may be ovarian cancer.

[0050] The cancer can be a cancer that is resistant to treatment with a DDR inhibitor, such as a PARP inhibitor. In certain embodiments, resistance to DDR inhibitor therapy, such as resistance to PARP inhibitor therapy, is caused by restoration of homologous recombination repair (HRR) in a previously HR-deficient cancer. Thus, in certain embodiments, the cancer is a previously HR-deficient cancer in which PARP inhibitor therapy results in restoration of homologous recombination repair, thereby resulting in resistance to PARP inhibitor therapy.

[0051] The method can include the step of evaluating a subject with cancer to identify the genetic or epigenetic makeup of the subject's cancer cells. In particular, the tumors of a subject with cancer can be systematically surveyed to identify potential somatic genetic changes in sequence, expression, and copy number. In particular, the method can include the step of analyzing one or more tumors or cancer cells of a subject with cancer for the presence of one or more deleterious mutations in genes associated with HR defects. Routine testing of the subject's HRD status can be performed to predict the subject's response to treatment with an RBM39 degrader, thereby helping clinicians determine the best treatment for their patients.

[0052] Additionally or alternatively, the cancer may be characterized by overexpression or amplification of RNA-binding motif protein 39 (RBM39) and / or DDB1 and CUL4-associated factor 15 (DCAF15). As disclosed herein, RBM39 expression has been found to be amplified or upregulated in certain cancers (e.g., KRAS mutant cancers, acute myeloid leukemia, colon cancer, breast cancer). Additionally, as disclosed herein, DCAF15 expression is amplified or upregulated in certain cancers (e.g., neuroblastoma, hematopoietic cancers, lymphoid cancers). Thus, the methods disclosed herein may include the step of assessing a subject for overexpression or amplification of RNA-binding motif protein 39 (RBM39) and / or DDB1 and CUL4-associated factor 15 (DCAF15). Cancers resistant to DDR inhibitor therapy, such as PARP inhibitor therapy

[0053] Cancer may be resistant to treatment with a DDR inhibitor (such as a PARP inhibitor). Cancer may be resistant to treatment with a DDR inhibitor (such as a PARP inhibitor) alone, i.e., when a subject is treated with a DDR inhibitor as a single active agent. Additionally or alternatively, cancer may be resistant to treatment with a DDR inhibitor (such as a PARP inhibitor) in combination with an anti-vascular endothelial growth factor (VEGF) inhibitor. As used herein, the term "resistant" or "resistance" to therapy refers to a lack of a beneficial response or a reduction in a beneficial response to treatment with a DDR inhibitor (such as a PARP inhibitor). A subject may initially show a beneficial response to treatment, but when the subject becomes resistant to treatment, the beneficial response may cease or decrease. In certain aspects, when a cancer is resistant to a DDR inhibitor therapy (such as a PARP inhibitor therapy), the cancer may have a homologous recombination defect. In certain embodiments, resistance to DDR inhibitor therapy, such as resistance to PARP inhibitor therapy, is caused by the restoration of homologous recombination repair (HRR) after treatment with a DDR inhibitor (such as a PARP inhibitor). RNA-binding motif protein 39 (RBM39) degrader

[0054] As used herein, the term "RNA-binding motif protein 39 (RBM39) degrader" refers to a compound that can be used to target RBM39, thereby causing RBM39 degradation. The RBM39 degrader can act as a molecular glue degrader of RBM39 by forming a ternary complex with RBM39 and the E3 ubiquitin ligase receptor DDB1 and CUL4-associated factor 15 (DCAF15), promoting the interaction between the RBM39 splicing factor and the CUL4-DCAF15 E3 ubiquitin ligase, thereby leading to polyubiquitination and proteasomal degradation of RBM39.

[0055] The RBM39 degrader can be an arylsulfonamide. The arylsulfonamide can be indifonamide, tassolan, CQS, E7820 or compound A. Compound A has the structure The RBM39 degrading agent may be E7820. The RBM39 degrading agent may be Compound A.

[0056] As used herein, the term "RBM39 degrader" is understood to encompass pharmaceutically acceptable salts thereof. As used herein, the term "RBM39 degrader" may refer to one RBM39 degrader or a combination of two or more RBM39 degraders. Combination therapy

[0057] Treatment with an RBM39 degrader can be combined with one or more additional cancer therapies. Thus, the method can further include administering the additional cancer therapy to the subject. The RBM39 degrader and the additional cancer therapy can be administered simultaneously, sequentially, or separately. The RBM39 degrader and the additional cancer therapy can be administered in combination. The RBM39 degrader can be administered simultaneously with, before, or after the additional cancer therapy.

[0058] The additional treatment may be any other treatment suitable for treating cancer, for example, chemotherapy or an immune checkpoint inhibitor.

[0059] In particular, the additional cancer treatment may be a DDR inhibitor, such as a PARP inhibitor, an ATR inhibitor or a CHK1 inhibitor. Therefore, the method may further comprise the step of administering a DDR inhibitor (such as a PARP inhibitor) to the subject. The RBM39 degrader and the DDR inhibitor (such as a PARP inhibitor) may be administered simultaneously, sequentially or separately. The RBM39 degrader and the DDR inhibitor (such as a PARP inhibitor) may be administered in combination. The RBM39 degrader may be administered simultaneously with, before or after the DDR inhibitor (such as a PARP inhibitor). The DDR inhibitor may be selected from the group consisting of inhibitors of WEE, RAD51, ATR, PolTheta, BLM, WRN, PARG, USP1 and DNAPKc.

[0060] When combined with DDR inhibitors (such as PARP inhibitors), RBM39 degraders can be used to induce a synthetic lethal phenotype, thereby enabling treatment of patients who would not benefit from treatment with DDR inhibitors in the absence of the RBM39 degrader.

[0061] Furthermore, RBM39 degraders and DDR inhibitors (such as PARP inhibitors) may have a synergistic effect in cancer treatment that is greater than the additive effect of each of the RBM39 degraders and DDR inhibitors (such as PARP inhibitors) when administered alone. In particular, it has been demonstrated that when RBM39 degradation is combined with PARP inhibition, the time to complete cancer regression is shortened compared to RBM39 degradation alone.

[0062] Treatment can be administered alone or as a pharmaceutical composition, which typically comprises a suitable pharmaceutically acceptable excipient, diluent or carrier. Pharmaceutically acceptable excipients, diluents or carriers can be selected according to the intended route of administration. Examples of suitable pharmaceutical carriers include water, glycerol and ethanol. Single agent

[0063] The RBM39 degrader can be administered as a single agent for treating cancer. In this embodiment, no additional cancer treatment, such as a PARP inhibitor, is administered. However, the treatment can still be administered as a pharmaceutical composition, which typically comprises a suitable pharmaceutically acceptable excipient, diluent, or carrier. In certain embodiments, the subject has previously undergone treatment with a PARP inhibitor prior to initiating treatment with the RBM39 degrader. Composition

[0064] Also provided herein are compositions comprising an RNA binding motif protein 39 (RBM39) degrader and a DNA repair and DNA damage response (DDR) inhibitor.

[0065] The RBM39 degradation agent may be an arylsulfonamide. The arylsulfonamide may be selected from the group consisting of indasulfanilamide, tassoran, CQS, and E7820. The RBM39 degradation agent may be E7820.

[0066] The DDR inhibitor may be a poly (ADP-ribose) polymerase (PARP) inhibitor. The DDR inhibitor may be an ATR inhibitor. The DDR inhibitor may be a CHK1 inhibitor. The PARP inhibitor may be selected from the group consisting of: olaparib, niraparib, talazoparib, and rucaparib. The PARP inhibitor may be olaparib. The PARP inhibitor may be niraparib. The DDR inhibitor may be a CHK1 inhibitor. The DDR inhibitor may be selected from the group consisting of: inhibitors of WEE, RAD51, ATR, PolTheta, BLM, WRN, PARG, USP1, and DNAPKc.

[0067] The composition may comprise an arylsulfonamide and a PARP inhibitor. For example, the composition may comprise E7820 and olaparib. The composition may comprise E7820 and niraparib. The composition may comprise indasulfanilamide and olaparib. The composition may comprise indasulfanilamide and niraparib.

[0068] The composition can be provided as a pharmaceutical composition, which generally comprises a suitable pharmaceutically acceptable excipient, diluent, or carrier. The pharmaceutically acceptable excipient, diluent, or carrier can be selected based on the intended route of administration. Examples of suitable pharmaceutical carriers include water, glycerol, and ethanol. The composition or pharmaceutical composition can be used in the methods disclosed herein. Subjects

[0069] Typically, the terms "subject" and "patient" are used interchangeably herein. A "subject" is typically a mammal, more typically a human.

[0070] A subject with cancer may have a cancer with normal HR function. A subject with cancer may have a cancer with normal BRCA function. Alternatively, a subject with cancer may have a cancer with HR deficiency. In this case, the subject with cancer may have one or more deleterious mutations in the cancer in one or more genes associated with HR deficiency. The genes associated with HR deficiency may be selected from the group consisting of: BRCA genes, genes associated with the Fanconi anemia repair pathway, ATM, TP53, genes associated with the base excision repair pathway, genes associated with the non-homologous end joining pathway, and genes associated with the alternative end joining pathway. In particular, the subject may have one or more deleterious mutations in the BRCA1 and / or BRCA2 genes.

[0071] The subject may have a cancer that has developed resistance / is resistant to a previous cancer treatment (eg, previous treatment with a DDR inhibitor such as a PARP inhibitor).

[0072] The subject may have a BRCA-normal cancer that has developed resistance / is resistant to treatment with a DDR inhibitor (such as a PARP inhibitor).

[0073] Additionally or alternatively, the subject's cancer may be characterized by overexpression or amplification of RNA binding motif protein 39 (RBM39) and / or DDB1 and CUL4 associated factor 15 (DCAF15).

[0074] RBM39 degraders can be provided as first-line or second-line treatment. For subjects who have become resistant to first-line treatment with DDR inhibitors (such as PARP inhibitors), RBM39 degraders can be provided as second-line treatment. Application

[0075] The RBM39 degrader and / or DDR / PARP inhibitor may be administered in a therapeutically effective amount, which is an amount sufficient to show a benefit to the subject to which the treatment is administered. The actual dosage administered, as well as the rate and time course of administration, will depend on the nature and severity of the condition being treated, as well as factors such as the age, sex, and weight of the subject being treated, and the route of administration, and may be determined with appropriate reference to the above. Appropriate consideration should further be given to the characteristics of the treatment, such as its plasma lifetime in vivo and concentration in the formulation, as well as the route, site, and rate of delivery. The prescription of treatment, such as decisions regarding dosage, etc., is ultimately the responsibility of general practitioners and other physicians and is determined at their own discretion, and typically takes into account the condition to be treated, the condition of the individual patient, the delivery site, the method of administration, and other factors known to practitioners.

[0076] Dosage regimens may include a single administration or multiple administrations.The treatment may further be administered simultaneously, sequentially or separately with other therapeutic agents and drugs used to treat cancer.

[0077] Treatment can be administered to a subject in need of treatment via any suitable route. In particular, treatment can be systemically administered. Treatment can be administered orally or parenterally by injection or infusion. Examples of preferred routes of parenteral administration include, but are not limited to, intravenous, intracardiac, intraarterial, intraperitoneal, intramuscular, intracavitary, subcutaneous, transmucosal, inhalation, and transdermal administration. Route of administration can further include enteral administration, such as mucosal (including lung) and rectal administration. Treatment can be administered via nanoparticles, microspheres, liposomes, other microparticle delivery systems, or sustained-release formulations placed in certain tissues (including blood). Predicting response to therapy with RBM39 degraders

[0078] Further provided herein are methods of predicting the response of a subject with cancer to treatment with an RNA-binding motif protein 39 (RBM39) degrader.

[0079] The method can include determining the subject's response to treatment with a DNA repair and DNA damage response (DDR) inhibitor therapy, such as a poly (ADP-ribose) polymerase (PARP) inhibitor therapy. Subjects resistant to DDR inhibitor therapy may benefit from treatment with an RBM39 degrader.

[0080] The method may additionally or alternatively include using the subject's HRD status to predict their response to treatment with an RNA binding motif protein 39 (RBM39) degrader. Therefore, the method may include determining the subject's homologous recombination deficiency (HRD) status. In particular, subjects identified as having homologous recombination (HR)-deficient cancers may benefit from treatment with an RBM39 degrader as a single agent or in combination with a DDR inhibitor. Subjects identified as having homologous recombination (HR)-function normal cancers may benefit from treatment with an RBM39 degrader in combination with a DDR inhibitor. Therefore, the present disclosure provides the use of biomarkers for homologous recombination (HR)-deficient / HR-function normal cancers for assessing the likelihood that an RBM39 degrader will produce an anti-cancer effect in a cancer subject. The anti-cancer effect may be any effect that is beneficial for treating the subject. This includes reducing or inhibiting the progression, severity and / or duration of cancer or at least one symptom thereof, and includes curative, alleviating or preventive effects. The HRD / mutation status of cancer cells and / or tumors in cancer subjects can be systematically surveyed to identify underlying somatic genetic changes in sequence, expression, and copy number, and the subject can be treated based on the genetic or epigenetic makeup of the cancer cells.

[0081] Determining the HRD status of an experimenter can include quantifying loss of heterozygosity (LOH), telomeric allele imbalance and / or large-scale state transitions. Determining the HRD status of an experimenter can include determining whether there are one or more deleterious mutations in one or more genes associated with HR defects (such as breast cancer susceptibility genes 1 or 2 (BRCA1 or BRCA2), genes associated with Fanconi anemia repair pathways, ATM, TP53, genes associated with base excision repair pathways, genes associated with non-homologous end joining pathways, and genes associated with alternative end joining pathways). In particular, determining the HRD status of an experimenter can include determining whether there are one or more deleterious mutations in breast cancer susceptibility genes 1 and / or 2 (BRCA1 and / or BRCA2). Additionally or alternatively, determining the HRD status of an experimenter can include using one of the methods discussed above about HRD status.

[0082] The method may include the step of administering to the subject an RBM39 degrader.

[0083] The method may further comprise the step of administering to the subject a DNA repair and DNA damage response (DDR) inhibitor, such as a poly (ADP-ribose) polymerase (PARP) inhibitor.

[0084] When the subject is identified as having a homologous recombination (HR)-deficient cancer, an RBM39 degrader can be administered. When the subject is identified as having a homologous recombination (HR)-normal cancer, an RBM39 degrader can be administered. When the subject is identified as having a BRCA-normal cancer, an RBM39 degrader can be administered.

[0085] Subjects who have been identified as having HR-deficient cancers that are resistant to treatment with DDR inhibitors (such as PARP inhibitors) may also benefit from treatment with RBM39 degraders. Therefore, when the subject's HRD status is determined to be HR-deficient, the method may include a step of determining the subject's response to treatment with a DNA repair and DNA damage response (DDR) inhibitor (such as a PARP inhibitor), wherein a subject who has HR-deficient cancer that is resistant to treatment with a DDR inhibitor (such as a PARP inhibitor) may benefit from treatment with an RBM39 degrader. The method may include the step of administering an RBM39 degrader to a subject, wherein the subject has been identified as having HR-deficient cancer and is resistant to treatment with a PARP inhibitor. The method may also include the step of administering a DDR inhibitor (such as a PARP inhibitor) to the subject.

[0086] Additionally or alternatively, the method may include the step of assessing overexpression and / or amplification of cancer RNA-binding motif protein 39 (RBM39) and / or DDB1 and CUL4-associated factor 15 (DCAF15), wherein a subject having overexpression and / or amplification of RBM39 and / or DCAF15 may benefit from treatment with an RBM39 degrader. Thus, the method may include the step of administering an RBM39 degrader to a subject, wherein the subject is identified as having overexpression or amplification of RBM39 and / or DCAF15. definition

[0087] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure relates.

[0088] As used herein, the term "treatment" and related terms such as "treat" and "treating" mean reducing or inhibiting the progression, severity, and / or duration of a cancer or at least one symptom thereof. Thus, the term "treatment" refers to any regimen that can benefit a subject. Treatment can include curative, palliative, or preventative effects.

[0089] It will be appreciated that certain features of the invention described in the context of separate embodiments for clarity may also be provided in combination in a single embodiment. Conversely, different features of the invention described in the context of a single embodiment for simplicity may also be provided individually or in any suitable subcombination. Examples Example 1 - Efficacy of the RBM39 degrader E7820 alone and in combination with the PARP inhibitor olaparib in the HRD-negative high-grade serous ovarian cancer OVCAR3 CDX model Materials and Methods Cell Culture: OVCAR3 is a BRCA-normal, HRD-negative human ovarian cancer cell line. This cell line was obtained from Crown Biosciences, China, for in vivo testing. OVCAR3 human ovarian tumor cells were maintained in vitro in RPMI1640 supplemented with 20% fetal bovine serum and 10 μg / ml insulin at 37°C in a 5% CO2 atmosphere in air. Prior to tumor inoculation, cells were harvested during the exponential growth phase and quantified using a cell counter. Tumor inoculation: OVCAR-3 tumor cells (1×10 7 cells) for tumor development. Random assignment: Random assignment started when the mean tumor size reached approximately 88 mm. 3 The study began at 1:00 p.m. BALBc / nude mice were enrolled. All animals were randomly assigned to one of seven study groups. Randomization was performed using the "matched distribution" method. The day of randomization was designated as day 0. Tumor Growth Inhibition (TGI): Tumor Growth Inhibition (TGI): TGI methods are known in the art. Tumor volumes were measured in two dimensions using calipers three times per week after randomization and expressed in mm using the following formula: 3 Volume is expressed in units: V = (L x W x W) / 2, where V is the tumor volume, L is the tumor length (the longest tumor dimension), and W is the tumor width (the longest tumor dimension perpendicular to L). %TGI was calculated for all mice using the formula %TGI = (TV vehicle - TV treatment) / (TV vehicle - TV initial) * 100 (Wong, H et al., Clin Cancer Res., 2012, 18(14): 3846-3855). Treatment groups: 10 mice per group were treated with vehicle, olaparib, E7820, E7820 plus olaparib, or paclitaxel for 21 days. Olaparib was administered at 100 mg / kg PO QD, E7820 was administered at 50 mg / kg PO BID, and paclitaxel was administered at 15 mg / kg IV QW. result The results are shown in Figure 1A (tumor volume) and Figure 1B (Tumor Growth Inhibition (TGI)). Figure 1A The results showed that treatment with 50 mg / kg of single-agent E7820 and a combination of 50 mg / kg of E7820 plus 100 mg / kg of olaparib reduced tumor volume in the HRD-negative OVCAR3 CDX model and was resistant to treatment with olaparib. Therefore, in this HRD-negative model, RBM39 degradation alone or in combination with PARP inhibition is superior to PARP inhibition alone. Example 2 - Immunohistochemistry (IHC) protein expression analysis of DNA damage response proteins and cell cycle checkpoint proteins in the tumor samples of Example 1 Materials and Methods • Sample Collection: From the in vivo OVCAR3 CDX study described in Example 1, 16 tumor samples were collected in the vehicle, olaparib, E7820 single-agent, and paclitaxel groups. Primary Antibody: Secondary Antibody Detection Kit Isotype Tissue processing 1) Collect fresh specimens and place them in 10% NBF (neutral buffered formalin; fixative volume / tissue, 10-20 times) and fix them at room temperature for 24 hours. 2) Trim the fixed tissue to a thickness of 3-5 mm. 3) The tissue was transferred to an embedding cassette, which was quickly placed in deionized water for 30 minutes, with the water being changed twice every 30 minutes. 4) After washing, the fixed tissue was transferred to a Leica ASP300S vacuum tissue processor for dehydration. Dehydration program Automated dehydration program Reagents Duration Temperature Pressure / vacuum 70% ethanol 20 minutes* RT — 80% ethanol 20min RT — 90% ethanol 20min RT — 95% ethanol 25min RT Open 100% ethanol 25min RT — 100% ethanol 35min RT — 100% ethanol 35min RT Open Xylene 35min RT — Xylene 35min RT Open Paraffin I 30min 60 — Paraffin II 30min 60 — Paraffin III 30min 60 Open *Note: When "Pressure / Vacuum" is turned on, pressure and vacuum will be in a cyclic operation state. Fluid is output when pressurized and fluid is returned when vacuum is on. *The duration of the first step can be extended moderately without affecting the final result. Preparation of FFPE blocks The sample is then embedded in a standard FFPE block using standard embedding procedures. The tissue is then embedded in paraffin in a paraffin embedding station. The sample label contains the mouse ID number and other information. Preparation of FFPE sections FFPE blocks were sectioned using a manual rotary microtome at a thickness of 4 μm per section. The sections were labeled with all necessary information for each sample, including project code, target name, group number, tissue type, etc. IHC program for the Bond RX automatic stainer *Note: RT: room temperature; ER1: epitope retrieval solution 1: (citrate buffer (pH 6.0)) for antigen retrieval; ER2: epitope retrieval solution 2: (EDTA buffer (pH 9.0)) for antigen retrieval; time = 0 means that the sections will be rinsed very quickly with solution; use The sections were mounted with Gold anti-fluorescence fading mounting medium (catalog number: S36938, Invitrogen). Data Analysis All stained sections were scanned at 40x magnification using the NanoZoomer-HT 2.0 imaging system. High-resolution images of the entire section were generated and further quantitative analysis was performed using HALO. TM The platform analyzes all scanned images. The entire slice image is analyzed and necrotic and interstitial areas are excluded, and only active tumor areas are scored. The intensity of specific staining is scored according to the following four levels: 0 (negative), 1+ (weak staining), 2+ (moderate staining), 3+ (strong staining). The percentage of tumor cells at different intensity levels is assessed using the H score. H score = (% of level 0) × 0 + (% of level 1) × 1 + (% of level 2) × 2 + (% of level 3) × 3 (H score ranges from 0 to 300). result The results are shown in Figures 2A-2H E7280 was found to be able to downregulate BRCA1 protein expression in OVCAR3 tumor samples ( Figure 2A ) and up-regulated the pHH3 protein expression in this sample ( Figure 2C ), while no significant changes were observed with olaparib treatment. This provides evidence that E7820 can directly affect the homologous recombination machinery. In addition, no changes in the expression of MCL1, CDK7, CDK9, CDK12, and CDK1 / 2 / 3 / 5 proteins were observed with E7820. This data provides evidence that RBM39 degradation can reduce the DDR repair machinery and promote cell cycle progression by crossing the G2 / M checkpoint and driving unrepaired cells into mitosis, without globally affecting the function of cyclin-dependent kinase proteins. Example 3 - Efficacy of the RBM39 degrader E7820 alone and in combination with the PARP inhibitor olaparib in the BRCA-normal ovarian cancer OV0273 PDX model Materials and Methods Tumor Inoculation: The study was conducted at Crown Biotech Co., Ltd. in China. Tumor fragments were harvested from primary mice and used for inoculation. Each mouse was inoculated subcutaneously with a primary human ovarian tumor xenograft model, OV0273, with a tumor fragment (2-3 mm in diameter), in the right upper flank for tumor development. Randomization: Randomization started when the mean tumor size reached approximately 149 mm. 3 The study began at 1:00 PM and enrolled 40 female BALB / c nude mice. All animals were randomly assigned to one of four study groups. Randomization was performed using the "matched distribution" method. The day of randomization was designated as day 0. Tumor Growth Inhibition (TGI): Tumor Growth Inhibition (TGI): TGI methods are known in the art. Tumor volumes were measured in two dimensions using calipers three times per week after randomization and expressed in mm using the following formula: 3 Volume is expressed in units: V = (L x W x W) / 2, where V is the tumor volume, L is the tumor length (the longest tumor dimension), and W is the tumor width (the longest tumor dimension perpendicular to L). %TGI was calculated for all mice using the formula %TGI = (TV vehicle - TV treatment) / (TV vehicle - TV initial) * 100 (Wong, H et al., Clin Cancer Res., 2012, 18(14): 3846-3855). Treatment Groups: Ten mice per group were treated for 28 days with vehicle, olaparib, E7820, or E7820 plus olaparib. Olaparib was administered at 90 mg / kg PO every day, and E7820 was administered at 85 mg / kg PO every day. The vehicle formulation matched that of E7820 and followed previous publications. E7820 was administered every 12 hours. result The results are shown in Figure 3A (tumor volume) and Figure 3B (Tumor Growth Inhibition (TGI)). Figure 3A The results showed that treatment with 85 mg / kg of single-agent E7820 and a combination of 85 mg / kg of E7820 plus 90 mg / kg of olaparib reduced tumor volume in the BRCA-normal OV0273 PDX model and was resistant to treatment with olaparib. Therefore, in the BRCA-normal ovarian PDX mouse model, RBM39 degradation alone or in combination with PARP inhibition was superior to PARP inhibition alone. The results of tumor growth curves of individual mice are shown in Figure 4A (E7820 monotherapy) and Figure 4B (combination of E7820 plus olaparib). Figure 4A and 4B All mice continued to maintain complete remission after 28 days of treatment, with two mice in the 85 mg / kg E7820 monotherapy group experiencing tumor regrowth starting around day 48, while zero mice in the 85 mg / kg E7820 plus 90 mg / kg olaparib combination group remained tumor-free at the same time point (day 48). In a BRCA-normal ovarian PDX mouse model, RBM39 degradation alone or in combination with PARP inhibition was sufficient to produce a potent and durable response. The survival analysis of each group in this study is shown in Figure 5 In the BRCA-normal OV0273 PDX model, 85 mg / kg of single-agent E7820 and the combination of 85 mg / kg of E7820 plus 90 mg / kg of olaparib extended median survival by >70 days compared to the vehicle control group and olaparib groups, with statistically significant differences observed (p<0.0001). The log-rank test was used to test the significance of the Kaplan-Meier analysis. In the BRCA-normal ovarian PDX mouse model, RBM39 degradation alone or in combination with PARP inhibition was sufficient to produce a survival benefit. The results of time to complete resolution are shown in Figure 6In a BRCA-normal ovarian PDX mouse model, on day 14, 10% of mice treated with 85 mg / kg of single-agent E7280 achieved complete remission (n=1), while 80% of mice treated with a combination of 85 mg / kg of E7820 plus 90 mg / kg of olaparib achieved complete remission (n=8). The difference in proportions between the groups was determined using a chi-square test. The difference between the combination group and the single-agent group was statistically significant (p<0.01). Therefore, the combination of RBM39 degradation and PARP inhibition was superior to that observed with RBM39 degradation alone in achieving complete remission faster, indicating a synergistic effect of the combination. Example 4 - Efficacy of the RBM39 degrader E7820 alone and in combination with the PARP inhibitor olaparib in the BRCA-normal ovarian cancer OV90 CDX model Materials and Methods Cell Culture: OV90 is a BRCA-positive human high-grade serous ovarian cancer cell line. LabCorp obtained this cell line from ATCC for in vivo testing. OV90 human ovarian tumor cells were maintained in vitro in DMEM, 10% NH1FBS, and 1% PSG. Tumor inoculation: NSG female mice were subcutaneously inoculated with serum-free DMEM OV90 tumor cells (1×10 ^6 Trypan blue-excluded cells) for tumor development. Random Assignment: All mice were assigned to study groups based on caliper estimates of tumor burden. Mice were assigned to ensure that the mean tumor burden of all groups was within 10% of the mean tumor burden of the study population. The mean estimated tumor burden of all groups in the experiment on the first day of treatment was 123mm 3 All animals weighed at least 14.9 g at the start of therapy, with an overall mean weight of 20.9 g. Tumor burden and body weight were well matched across all groups in the experiment (within 10% of the overall mean). Tumor Growth Inhibition (TGI): Tumor Growth Inhibition (TGI): TGI methods are known in the art. Tumor volumes were measured in two dimensions using calipers three times per week after randomization and expressed in mm using the following formula: 3Volume is expressed in units: V = (L x W x W) / 2, where V is the tumor volume, L is the tumor length (the longest tumor dimension), and W is the tumor width (the longest tumor dimension perpendicular to L). %TGI was calculated for all mice using the formula %TGI = (TV vehicle - TV treatment) / (TV vehicle - TV initial) * 100 (Wong, H et al., Clin Cancer Res., 2012, 18(14): 3846-3855). Treatment groups: Ten mice per group were treated for 21 days with vehicle, niraparib, olaparib, E7820, E7820 plus niraparib, or E7820 plus olaparib. Niraparib was administered at 40 mg / kg PO QD, olaparib was administered at 100 mg / kg PO QD, and E7820 was administered at 50 mg / kg PO BID. result The results are shown in Figure 7A (tumor volume) and Figure 7B (Tumor Growth Inhibition (TGI)). Figure 7A The results showed that in the BRCA-normal OV90 CDX model, the tumor volume was reduced in the combination of niraparib 40 mg / kg plus 50 mg / kg of E7820 and the combination of olaparib 100 mg / kg plus 50 mg / kg of E7820 compared to both the single-agent niraparib group and the olaparib group, and the tumors were resistant to the single-agent niraparib treatment group and the olaparib treatment group, respectively. The difference was statistically significant using a two-way ANOVA analysis (p < 0.0001). Therefore, in the ovarian CDX mouse model with normal BRCA function and resistance to PARP inhibitors, RBM39 degradation combined with PARP inhibition is superior to PARP inhibition alone. Example 5 - CellTiter-Glo Assay for Assessing the Effects of RBM39 Degraders on In Vitro Cell Viability and Proliferation of OVCAR3 Cell Lines Materials and Methods Figure 8A : Cell Culture: OVCAR3 is a BRCA-normal, HRD-negative human ovarian cancer cell line. This cell line was obtained from Pharmaron, China, for in vitro testing. OVCAR3 human ovarian tumor cells were maintained in RPMI-1640 (Glutamax) supplemented with 0.01 mg / ml insulin, 20% FBS, and 1% PS. Cell inoculation: Harvest cells from culture flasks into cell culture medium and count. Dilute cells with culture medium to a low cell density and plate 8,000 OVCAR cells at 40 μL per well into a 384-well plate (PerkinElmer, catalog number: 6007680) using an electronic multichannel pipette. For low control wells, add 40 μL of PBS. Cover the plate and rotate at 1000 rpm for 1 min, then incubate overnight at 37°C, 5% CO2. Compound time: SR4835 and THZ531 were dissolved into 10 mM stock solutions and diluted in a 3-fold, 9-point dilution series. Cells were treated with 40 nL of SR4835 and THZ531 by plate formatting Echo550 and then incubated at 37°C in CO 2 Incubate in a culture medium for 72 h. For the high control, add 40 nL of DMSO. Readout: CellTiter- 2.0 reagent (Promega, G9242) was removed from the refrigerator and equilibrated at RT (23°C) for 60 minutes. The plate was removed from the incubator and allowed to equilibrate to room temperature for at least 15 minutes. 30 μL CellTiter- 2.0 reagent was added to the assay plate and allowed to stand for 30 minutes before reading. Luminescent signals were read on an Envision. Calculation: Calculate cell viability (% of DMSO control) using the following equation: ο100–100*(high control luminescence value–compound luminescence value) / (high control luminescence value–low control luminescence value) o High control = 0.1% DMSO o Low control = PBS wells Figure 8B : Cell Culture: OVCAR3 is a BRCA-normal, HRD-negative human ovarian cancer cell line. This cell line was obtained from Pharmaron Chemicals, Inc., China, for in vitro testing. OVCAR3 human ovarian tumor cells were maintained in RPMI-1640 (Glutamax) supplemented with 0.01 mg / ml insulin and 20% FBS. Cell seeding: Harvest cells from culture flasks into cell culture medium and count. Dilute cells with culture medium to a low cell density and plate 8,000 OVCAR cells at 50 μL per well into a 384-well plate (PerkinElmer, catalog number: 6007680) using an electronic multichannel pipette. For low control wells, add 50 μL of PBS. Cover the plate and rotate at 1000 rpm for 1 min, then incubate overnight at 37°C, 5% CO2. Compound Time: E7820 and indifonamide were dissolved into 10 mM stock solutions, and 50 nL was transferred to 10 μL of dilution solution. The solution was diluted in a 3-fold, 11-point dilution series in a 384LDV plate (LABCYTE, LP-0200). For the high control wells, 50 nL of DMSO was added. Cells were treated with E7820 and indifonamide using the plate reprogramming software Echo and spun at 1000 rpm for 1 min. The cells were then incubated at 37°C in a CO2 atmosphere. 2 Incubate in an incubator for 72 hours. Readout: CellTiter- 2.0 reagent (Promega, G9242) was removed from the refrigerator and equilibrated at RT (23°C) for 60 minutes. The plate was removed from the incubator and allowed to equilibrate to room temperature for at least 30 minutes. 40 μL CellTiter- 2.0 reagent was added to the assay plate and spun at 1 min / 1000 rpm and then allowed to stand for 20 minutes before reading. Luminescent signals were read on an Envision. Calculation: Calculate cell viability (% of DMSO control) using the following equation: ο100–100*(high control luminescence value–compound luminescence value) / (high control luminescence value–low control luminescence value) o High control = 0.1% DMSO o Low control = PBS wells result Cell viability results are shown in Figure 8A (using the CDK12 / 13 inhibitors THZ531 and SR4835) and Figure 8B (using the RBM39 degraders E7820 and indifamide). Figure 8A The results showed that OVCAR3 cells treated with THZ531 or SR4835 showed a dose-dependent decrease in cell viability. Figure 8B The results showed that treatment with E7820 or indifonamide had minimal effects on cell viability in OVCAR3 cells. In an HRD-negative ovarian cancer cell line, RBM39 degradation did not affect cell viability, whereas CDK12 / 13 inhibition demonstrated a dose-dependent decrease in cell viability. Thus, when treated in vitro, RBM39 degradation was significantly less cytotoxic to OVCAR3 cells than CDK12 / 13 inhibition. Example 6 - NanoBRET Target Engaged Intracellular Kinase Assay for Assessing the Effects of RBM39 Degraders on CDK12+ Cyclin K Kinase Activity Materials and Methods Cell culture: CDK12 NanoBRET assay kit was obtained from Reaction Biology, and experiments were performed by Pharmaron. HEK293 cells were cultured in 90% DMEM with 10% FBS. Cells were cultured in T-75 flasks at 37°C and 5% CO. 2 Culture in a cell culture incubator at 95% relative humidity. Once cells reach 80%-90% confluence, they are detached and passaged. Rinse the cultured cells in the T-75 flask with 5 mL of PB and aspirate. Add 1.5 mL of trypsin and incubate at 37°C for approximately 5 minutes or until the cells detach and begin to float. Inactivate the trypsin by adding culture medium containing excess serum. Transient transfection of HEK293 cells: Remove the cell culture medium from the cell culture flask by aspiration and trypsinize to detach the cells from the flask. Neutralize the trypsin with cell culture medium and pellet the cells by centrifugation at 200 x g for 5 minutes. Aspirate the medium and resuspend in assay medium consisting of 99% Opti-MEM (reduced serum medium without phenol red) and 1% FBS. Adjust the density to 2 x 10 cells using assay medium. 5 cells / ml. A 10 μg / ml DNA solution in Opti-MEM was prepared, which consisted of 9 μg / mL CCNK, 1 ug / mL kinase-NanoLuc fusion vector DNA CDK12 and 1 mL of Opti-MEM. The solution was thoroughly mixed. 30 μl of FuGENE HD transfection reagent was added to each milliliter of DNA mixture to form a lipid:DNA complex. The mixture was inverted 5-10 times and incubated at ambient temperature for 20 minutes to allow the complex to form. In a sterile conical tube, 1 part of the lipid DNA complex (1 mL) was mixed with 20 parts of HEK293 cells (20 mL, at 2x 10 5 Mix the cells with a 50 μL suspension (100 cells / mL). Gently mix by inverting the tube 5 times. Then, aliquot 40 μL of the cell + lipid:DNA complex into a sterile tissue culture-treated 384-well assay plate and incubate for 20-30 hours. Add NanoBRET tracer reagent to the cells. Dilute 5 compounds (E7820, indifamide, THZ531, CR8, and AT7519) to 10uM in DMSO (in 3-fold, 10-point dilutions each). Transfer 40nL of each compound concentration to a 384-well plate via Echo. Prepare 400μM NanoBRET tracer reagent and add 100nL of tracer to the 384-well plate. Then incubate the plate at 37°C, 5% CO 2 Incubate for 2 hours. A 3X complete substrate plus inhibitor solution in reduced serum medium (without phenol red) was prepared as follows: 48 μL NanoBRET Nano-Glo substrate; 16 μL extracellular NanoLuc inhibitor; 7936 μL Opti-MEM reduced serum medium (without phenol red). Finally, 20 μL of this 3X complete substrate plus inhibitor solution was added to each well of a 384-well plate and incubated at room temperature for 2-3 minutes, and the plate was read on an Envision. Calculation: The BRET ratio is calculated as follows: o BRET ratio = acceptor sample / donor sample x 1000 o High control = cells + DMSO + tracer o Low control = cells + 30uMAT7519 + tracer result The CDK12 kinase activity results of the CDK12 / 13 inhibitor THZ531, the CDK12 degrader CR8, the RBM39 degraders E7820 and indifonamide, and the pan-CDK inhibitor AT7519 are shown in Figure 9 RBM39 degradation did not affect CDK12 kinase activity, whereas CDK12 / 13 inhibition demonstrated dose-dependent inhibition of kinase function. Thus, in vitro, RBM39 degradation had no effect on CDK12 activity compared to CDK12 / 13 inhibition or CDK12 degradation. Example 7 - Analysis of DDR gene expression in OVCAR3 cells treated with the RBM39 degrader E7820 Figure 10A : Materials and Methods Cell Seeding: Harvest OVCAR3 cells from the culture flask into cell culture medium and count the cells. Dilute the cells to 1e6 cells / well in culture medium and seed each well of a 6-well cell culture plate. Cover the plate and gently shake it. Incubate at room temperature for 30 minutes, then transfer to a 37°C, 5% CO2 incubator overnight to allow the cells to adhere. Compound Treatment: Dissolve E7820 in a 10 mM DMSO stock solution and dilute it three-fold, with a maximum concentration of 10 mM, over five doses. Add the dilution series at a 1 / 1000 dilution and treat for 6 hours. Six replicate wells were set for each concentration. Cell pellets were harvested and total RNA was isolated. RNA purification: RNA was purified using the PureLink RNA Mini Kit (Invitrogen, 12183018A). 300 μL of lysis buffer with 1%-2% mercaptoethanol was added to the sample and the cells were lysed on ice for 20 minutes. The lysate was centrifuged at 12,000 rpm for 15 minutes, and the supernatant was transferred to a clean, RNase-free tube. One volume of 70% ethanol was added to each volume of cell lysate and vortexed. A maximum of 700 μL of sample was transferred to a spin column and centrifuged at 12,000 g for 15 seconds at RT. Flow-through was discarded and repeated until all samples were processed. 700 μL of wash buffer I was added to the spin column and centrifuged at 12,000 g for 15 seconds at RT. Flow-through was discarded. Next, 500 μL of wash buffer II with ethanol was added to the spin column and centrifuged at 12,000 g for 15 seconds at RT. Flow-through was discarded and repeated. After washing, centrifuge the spin column at 12,000 g for 2 minutes to dry the membrane with bound RNA. Add 30 μL of RNase-free water to the center of the spin column and incubate at room temperature for 1 minute. Then centrifuge the spin column for 2 minutes to elute the RNA from the membrane into a recovery tube. The purified RNA can then be stored. Calculation: Quantify RNA concentration using Nano-Drop. Reverse transcribe RNA into cDNA using the High-Capacity RNA-to-cDNA Kit (Invitrogen, 4387406). Use three housekeeping genes (ACTB, GAPDH, 18S) as references. Calculate ΔCT using the following equation: ΔCT = CT 靶标 -CT 参考基因 , for E7280 at the highest concentration of 0 uM to 10 uM. Relative mRNA expression (ΔΔCT) was calculated as ΔΔCT = 2 -ΔCT The relative expression (fold relative to DMSO) was calculated, and the error bars in the figures are shown as SEM. Figure 10B : Materials and Methods 1. Reagents for in vitro analysis 2. Consumables for in vitro analysis 3. Instruments for in vitro analysis instrument supplier model Countess Yingjie Company centrifuge Eppendorf 5810R Vortex mixer Aika MS3 Digital QuantStudio7Flex Real-Time PCR System Applied Biosystems 4484643 4. Cell Lines cell lines culture medium OVCAR3 RPMI-1640 + 0.01 mg / ml insulin + 20% FBS Cell Seeding: Harvest OVCAR3 cells from the culture flask into cell culture medium and count the cells. Dilute the cells to 300,000 cells / well with culture medium and add 2000 μL of the cell suspension to each well of a 6-well cell culture plate. Cover the plate and gently shake it. Incubate at room temperature for 30 minutes, then transfer to a 37°C, 5% CO2 incubator overnight to allow the cells to adhere. Compound Treatment: Dissolve E7820 into a 10 mM DMSO stock solution and dilute to 3 mM by transferring 6 μL of the stock solution into 14 μL DMSO. Then, dilute the compound to 0.3 mM by transferring 2 μL of the 3 mM diluted compound into 18 μL DMSO. Transfer 2 μL of the diluted compound from the compound source plate to the cell plate, giving final concentrations of 0.3 μM and 3 μM, respectively. For the negative control, use 2 μL DMSO. Gently shake the plate at 200 RPM for 1 minute at room temperature. Incubate the compound treatment in a 37°C, 5% CO2 incubator for 24 hours. ·Cell harvesting and storage: Prepare lysis buffer with 1% β-ME (600μl / well, 6-well plate). After 24 hours of compound treatment, remove the culture medium by aspiration and wash the cells in each well with 2ml of cold 1xPBS. Add 600μl of lysis buffer (+1% β-ME) to each well of the 6-well plate. Use a 1000μl pipette to transfer the cell lysate (approximately 600ul) to a labeled 1.5ml vial. Next, prepare 70% ethanol with nuclease-free water. Add 1 volume (600μl) of 70% ethanol to each vial and mix thoroughly by pipetting up and down 3 times. Load the lysate onto the QiaShredder column and spin at 12000rpm for 15sec. Collect the flow-through and transfer the remaining 600μL sample to the same column to collect the flow-through. Transfer 600 μL of the flow-through sample to an RNeasy spin column placed in a 2 mL collection tube and centrifuge at 12,000 rpm for 15 seconds at RT, discarding the flow-through. Transfer the remaining 600 μL of sample to the same column and centrifuge at 12,000 rpm for 15 seconds at RT, discarding the flow-through. Place the RNeasy spin column in a new collection tube. Add 500 μL of wash buffer to the RNeasy spin column and centrifuge at 12,000 rpm for 15 seconds at RT, discarding the flow-through. Centrifuge again at 12,000 rpm for 2 minutes at RT. Place the RNeasy spin column in a new collection tube with a cap. Add 30 μL of RNase-free water directly to the column membrane and incubate at RT for 2 minutes, followed by centrifugation at 12,000 rpm for 2 minutes at RT. Assay the RNA samples using a Nanodrop and store the RNA at -80°C. ·RNA extraction and qPCR operation: Thaw the total RNA and RNA samples on ice. Prepare RT master mix (10μl 2XRT buffer + 1μl 20XRT enzyme mix) at RT. Use a pipette to distribute 11μL RT master mix into each well of a 96-well qPCR plate in rows. Use a pipette to transfer 2μg RNA sample to a 96-well qPCR plate. In addition, use a pipette to transfer 2μg RNA sample and 2μL internal control RNA to a 96-well qPCR plate. The total volume of each reaction is 20, so the remaining volume is made up with H20. Rotate the plate for 1 minute and perform the RT reaction (incubate at 37°C for 1 hour, then incubate at 95°C for 5 minutes to inactivate the enzyme, and keep at 4°C indefinitely). Prepare the qPCR mixture at RT. 10 μL of qPCR mixture was dispensed into the corresponding wells of the UPHS-029ZE QuantiNova LNA probe focus panel (QIAGEN, 249955). The reaction was sealed with optical adhesive film and then briefly centrifuged to allow the PCR reaction mixture to settle to the bottom of the plate. The experiment was then set up using the following conditions. Calculation: Normalized fold expression. The calculation of normalized fold expression is known in the art. ΔCT is calculated by using the following equation: ΔCT = CT 靶标 -CT 参考基因 The relative mRNA expression (ΔΔCT) was calculated as ΔΔCT = 2 -ΔCT The expression folds were then normalized to the geometric mean of five housekeeping genes (ACTB, B2M, GAPDH, HPRT1, and RPLP0) to calculate the expression folds (Taylor SC et al. Trends Biotechnol., 2019, 37(7): 761-774). result · Figure 10A Shown are the gene expression levels of BRCA1 and ATR at five doses after OVCAR3 cells were treated with E7820 for 6 hours. Figure 10BFigure 3 shows the gene expression levels of a panel of DNA repair genes (RAD50, RAD18, TOPBP1, FANCD2, XRCC1), cellular checkpoint genes (ATM, CHEK1), and CDK7 in OVCAR3 cells treated with 0.03uM E7820 for 24 hours. RBM39 degradation showed a dose-dependent decrease in key genes regulating homologous recombination and cell cycle checkpoints; however, targets such as CHEK1 and CDK7 remained relatively stable, indicating that RBM39 degradation can induce specific downregulation of DDR genes without affecting the expression of dose-limiting toxicity-related genes (such as CHEK1 and CDK7). These figures demonstrate that RBM39 degradation is sufficient to induce the BRCAness phenotype in vitro. Example 8 - Efficacy and target engagement of Compound A alone and in combination with the PARP inhibitor niraparib in Balb / C nude mice in the BACA-normal ovarian cancer OV0273 PDX model Materials and Methods Tumor inoculation: Tumor fragments from female Balb / C nude mice were harvested and used for inoculation into mice. Primary human ovarian tumor xenograft model OV0273 tumor fragments (2-3 mm in diameter) were inoculated subcutaneously in the right upper flank of each mouse for tumor development. Randomization: Randomization starts when the average tumor size reaches approximately 150-200 mm 3 The study began at 1:00 PM. Thirty-two mice were enrolled for the in vivo efficacy portion of the study, and 12 mice were enrolled for the pharmacodynamic tumor marker portion. All animals were randomly assigned to four study groups. Randomization was performed using a "matched distribution" approach. The day of randomization was designated as day 0. Tumor size was shared between treatment groups after randomization. Western blotting: Western blotting methods are known in the art. Tumor tissue samples from mice were transferred to 5 ml polypropylene tubes, weighed, and prepared with 3x volumes of lysis buffer (e.g., 300 ul lysis buffer for 100 mg tumor sample). The samples were homogenized and then lysed for 30 min. The samples were then centrifuged at 14,000 g for 15 min at 4 ° C. The supernatant was transferred to a new tube. Protein quantification was performed according to the Pierce BCA protein assay kit (Thermo Fisher). Each PDX tumor protein lysate was loaded onto a precast gel (26-well, 4%-15%, Criterion TGX from Bio-Rad) at 50 ug / lane. The gel was run at a constant voltage (60 V). The PVDF membrane was pre-activated in methanol for 2 min, followed by pre-wetting the membrane and filter paper in cold transfer buffer. The gel membrane was sandwiched in the middle and protein transfer was started at 280 mA for 2 hours. The primary antibody was diluted in TBST containing 5% milk (1:1000) and incubated with gentle shaking at 4°C overnight. The membrane was washed three times in TBST for 5 minutes each. The membrane was then incubated with the secondary antibody diluted in TBST containing 5% milk for 1 hour at room temperature on a nutator. The membrane was washed three times in TBST for 5 minutes each, and the target protein was detected using the ECL method using a Tanon 5200 chemiluminescent image analysis system. The primary antibody used to detect RBM39 was obtained from MEC (Catalog No.: HPA001591). Caco-2 treated cells were used as a positive control. Tumor Growth Inhibition (TGI): Methods for assessing TGI are known in the art. Tumor volume was measured in two dimensions using calipers three times per week after randomization and expressed in mm using the following formula: 3 The volume is expressed in units: V = (L x W x W) / 2, where V is the tumor volume, L is the tumor length (the longest tumor dimension), and W is the tumor width (the longest tumor dimension perpendicular to L). %TGI was calculated for all mice using the formula %TGI = (TV vehicle - TV treatment) / (TV vehicle - TV initial) * 100 (Wong, H et al., Clin Cancer Res., 2012, 18(14): 3846-3855). Treatment Groups: 8 mice per group (efficacy) or 3 mice per group (PD markers) were treated with vehicle, niraparib, compound A, or compound A plus niraparib for 28 days (efficacy) or 3 days (PD markers). Niraparib was administered at 40 mg / kg PO QD and compound A was administered at 100 mg / kg PO BID. The vehicle formulation matched compound A. Compound A was administered BID at 12 hours. result The results are shown in Figure 11A (tumor volume), Figure 11B (tumor growth inhibition (TGI)) and Figure 11C (Western blot). Figure 11A The results showed that in the BRCA-normal OV0273 PDX model, tumor volume was significantly reduced using either single-agent Compound A (p<0.001) or a combination of Compound A and niraparib (p<0.001) compared to vehicle. This model was resistant to treatment with niraparib, while Compound A alone was superior to niraparib alone (p<0.05). Therefore, in the BRCA-normal ovarian PDX mouse model, RBM39 degradation alone or in combination with PARP inhibition was superior to PARP inhibition alone. Statistical analysis between groups was performed using one-way ANOVA and Tukey's multiple comparison test. Data were analyzed in GraphPadPrism 10.1.1. Figure 11C It was shown that compound A could effectively reduce the level of RBM39 in mouse tumors after 3 days of treatment.

Claims

1. A method for treating (i) a homologous recombination (HR)-deficient cancer, (ii) a homologous recombination (HR)-normal cancer, or (iii) a cancer resistant to DNA repair and DNA damage response (DDR) inhibitor therapy in a subject in need thereof, the method comprising administering to the subject an RNA binding motif protein 39 (RBM39) degrader in an amount effective to treat the cancer.

2. The method of claim 1, further comprising administering to the subject a DNA repair and DNA damage response (DDR) inhibitor in an amount effective to treat the cancer.

3. The method of claim 2, wherein the DDR inhibitor is a poly (ADP-ribose) polymerase (PARP) inhibitor.

4. The method of claim 3, wherein the PARP inhibitor is olaparib.

5. The method of any one of claims 1 to 4, wherein the cancer that is resistant to DDR inhibitor therapy is resistant to poly (ADP-ribose) polymerase (PARP) inhibitor therapy.

6. The method of any one of claims 1 to 5, wherein the cancer is selected from the group consisting of ovarian cancer, breast cancer, prostate cancer, gastric cancer, pancreatic cancer, KRAS mutant cancer, acute myeloid leukemia, colon cancer, neuroblastoma, hematopoietic cancer, lymphoid cancer, non-small cell lung cancer, and small cell lung cancer.

7. The method of claim 6, wherein the cancer is ovarian cancer.

8. The method of any one of claims 1 to 7, further comprising determining the homologous recombination deficiency (HRD) status of the subject.

9. The method according to any one of claims 1 to 8, further comprising determining the presence or absence of one or more deleterious mutations in one or more genes selected from the group consisting of: Breast cancer susceptibility gene 1 or 2 (BRCA1 or BRCA2), genes related to the Fanconi anemia repair pathway, ATM, TP53, genes related to the base excision repair pathway, genes related to the non-homologous end joining pathway, and genes related to the alternative end joining pathway.

10. The method according to any one of claims 1 to 9, further comprising determining the presence or absence of one or more deleterious mutations in BRCA1 and / or BRCA2.

11. The method according to any one of claims 1 to 10, further comprising assessing the subject for overexpression or amplification of RBM39 and / or DDB1 and CUL4-associated factor 15 (DCAF15).

12. The method according to any one of claims 1 to 11, wherein the RBM39 degrading agent is an arylsulfonamide.

13. The method according to claim 12, wherein the arylsulfonamide is E7820.

14. The method according to claim 12, wherein the arylsulfonamide is Compound A.

15. A composition comprising an RNA binding motif protein 39 (RBM39) degrader and a DNA repair and DNA damage response (DDR) inhibitor.

16. The composition of claim 15, wherein the DDR inhibitor is a poly (ADP-ribose) polymerase (PARP) inhibitor.

17. The composition of claim 15 or 16, wherein the RBM39 degrader is an arylsulfonamide.

18. The composition of claim 17, wherein the arylsulfonamide is E7820.

19. The composition of claim 17, wherein the arylsulfonamide is Compound A.

20. A method for predicting a subject's response to cancer treatment with an RNA-binding motif protein 39 (RBM39) degrader, the method comprising determining the subject's response to treatment with a DNA repair and DNA damage response (DDR) inhibitor therapy, and if the subject is identified as resistant to the DDR inhibitor therapy, administering the RBM39 degrader to the subject in an amount effective to treat the cancer.

21. The method of claim 20, further comprising administering to the subject a DNA repair and DNA damage response (DDR) inhibitor in an amount effective to treat the cancer.

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