海創(chuàng)藥業(yè)（688302.SH）6項研究成果在2024年美國癌癥研究協(xié)會(AACR)年會Late-Breaking Research（重磅摘要）環(huán)節(jié)上發(fā)布。轉化醫(yī)學部與生物部負責人李景博士和商務部負責人Agustin de la Calle博士出席了本屆AACR年會并作項目成果介紹。

*李景博士與Agustin de la Calle博士現(xiàn)場照片*

2024年度美國癌癥研究協(xié)會（American Association for Cancer Research, AACR）年會作為癌癥研究界的焦點，邀請了來自世界各地的癌癥科學家，共同分享和討論腫瘤領域的最新科學和醫(yī)學研究成果。AACR年會于當?shù)貢r間2024年4月5日至10日在美國加利福尼亞州圣地亞哥舉行。Late-Breaking Research是AACR年會中備受矚目的會議環(huán)節(jié)，該環(huán)節(jié)主要展示在腫瘤治療領域中最具有創(chuàng)新價值和臨床潛力的研究。海創(chuàng)藥業(yè)本次6項研究成果在Late-Breaking Research環(huán)節(jié)發(fā)布，標志著公司產品管線的創(chuàng)新力及臨床潛力得到國際認可。

摘要標題：

HP518, an oral AR-targeting PROTAC for the treatment of AR positive triple negative breast cancer with a novel mechanism of action

摘要作者：

J. Li, H. Yuan, K. Chen, Y. Huo, G. Liu, W. Du, X. Li;

Hinova Pharmaceuticals, Chengdu, China

摘要全文：

Triple negative breast cancer (TNBC) accounts for 15-20% of all breast carcinomas and has poor prognosis. Chemotherapy is the mainstay treatment for TNBC patients, yet with limited clinical benefit. Androgen receptor (AR) is expressed in approximately 50% of TNBC tumors and thus the anti-androgen therapy could be a promising solution for the treatment of AR TNBC. Nevertheless, AR inhibitors including enzalutamide and bicalutamide or the androgen biosynthesis inhibitor abiraterone have failed to demonstrate satisfying anti-tumor activity in clinical trials. We have discovered HP518, an AR-targeting PROTAC (proteolysis targeting chimera) that induces potent degradation of both the wild-type AR and AR mutants. HP518 is currently under the clinical development for the treatment of mCRPC. Here we report the preclinical data on HP518 for the treatment of AR TNBC. HP518 robustly degrades AR in multiple TNBC cell lines with a half-maximal degradation concentration (DC ) < 1 nM. HP518 strongly inhibits AR TNBC cell growth, whereas the AR inhibitor enzalutamide does not show significant antiproliferative effect on these cells in the presence or absence of androgen. Consistent with the in vitro results, HP518 significantly and dose-dependently inhibits tumor growth in MDA-MB-453 cell line derived tumor xenograft (CDX) and patient-derived xenograft (PDX) mouse models. PI3KCA activating mutations are frequently expressed in AR TNBC. HP518 in combination with alpelisib, a PI3Kα inhibitor shows a synergistic anti-tumor activity. Mechanistically, HP518, but not AR inhibitor enzalutamide downregulates the mRNA expression levels of a set of DNA replication-related genes in AR TNBC cells, indicating a novel and ligand-independent role for AR in regulating growth of AR TNBC cells. Therefore, HP518, an AR-targeting PROTAC degrader holds great potential to fulfill the unmet clinical needs for the AR TNBC therapy. Selected pre-clinical data will be presented. HP518 structure will not be disclosed.

摘要標題：

Identification of the highly potent and orally available ER-targeting PROTAC degrader HP568 for the treatment of breast cancer

摘要作者：

W. Du, Z. Tu, D. Qin, H. Li, J. Duan, S. Liu, M. Zhang, Z. Nie, Z. Yuan, J. Li, X. Li;

Hinova Pharmaceuticals, Chengdu, China

摘要全文：

Breast cancer remains an unmet medical need. It has become the most occurring and deadliest cancer for women globally. Estrogen receptor (ER) is expressed in 75% of breast cancers and has the key role in tumorigenesis and progression of ER breast cancers. Endocrine treatments that target ER are the mainstay therapies for the ER breast cancers, yet drug resistance unavoidably develops due to mutations in the ER gene. The ER-targeting proteolysis targeting chimera (PROTAC) degrader is an emerging new modality that interrupts the ER signaling through degradation of ER and offers unprecedented potential for solving the endocrine resistance. We have discovered HP568, an ER-targeting PROTAC that is highly potent against both the wild-type ER and ER mutants. HP568 has a favorable ADME profile that is superior to known competitor ER-targeting PROTAC. In the head-to-head comparison efficacy studies, HP568 has demonstrated the dose-dependent and superior efficacy that is well consistent with the drug exposure profile and PD biomarkers. HP568 also shows a synergetic effect in combination with a CDK4/6 inhibitor. HP568 is clean in the secondary pharmacology profiling, and well tolerated in animal tox studies. HP568 is under the preclinical development and has the potential to be the best-in-class ER-targeting degrader. HP568 structure will not be disclosed.

摘要標題：

Discovery of HP537, a potent and selective p300/CBP inhibitor for the treatment of hematologic malignancies

摘要作者：

J. Li, Z. Tu, J. Peng, L. Fan, H. Yu, F. Wang, X. Li;

Hinova Pharmaceuticals, Chengdu Shi, China

摘要全文：

E1A-binding protein P300 (p300) and its paralog CREB binding protein (CBP) are key acetyl transferases (HAT) and transcriptional co-factors. p300/CBP bromodomain (BRD) inhibition reduces acetylation of H3K27 at enhancers, leading to suppression of enhancer-driven gene expression, such as MYC and IRF4 that are critical for the initiation, progression, and chemoresistance of hematological malignancies. Thus, p300/CBP inhibition is a highly potential therapeutic strategy for the treatment of hematological malignancies, including multiple myeloma (MM), non-Hodgkin lymphoma (NHL) and leukemia. We have discovered HP537 that competitively inhibits an acetylated peptide substrate to bind BRD of p300/CBP with IC50 < 5 nM. HP537 does not inhibit the enzymatic activity of HAT domain of p300/CBP and HAT1, nor has binding affinity for other BRD containing proteins including BRD4 and BRD9. HP537 inhibits proliferation of a wide range of cell lines derived from MM, leukemia and lymphoma with IC50 values ranged from 0.01 μM to 0.4 μM. Protein expression levels of acetylated H3K27, c-Myc and IRF4 are significantly decreased by HP537 in MM, NHL and acute myelogenous leukemia (AML) cell lines in a dose- and time-dependent manner. HP537 robustly and dose-dependently inhibits tumor growth in OPM-2 (MM), MOLM-16 (AML), and KARPAS-422 (NHL) cell line derived tumor xenograft (CDX) mouse models. Down-regulation of c-Myc and IRF4 are also observed in the tumor samples. In conclusion, HP537 is a novel, potent and selective inhibitor of p300/CBP BRD. The pre-clinical data supports the clinical development of HP537 for the treatment of hematological malignancies. A FIH study of HP537 in cancer patients is planned to start in 2024. HP537 structure will not be disclosed.

摘要標題：

Discovery of HP560, a novel BET inhibitor for the treatment of myelofibrosis

摘要作者：

J. Li, L. Fan, H. Yuan, Y. Huo, H. Yu, F. Wang, X. Li;

Hinova Pharmaceuticals, Chengdu Shi, China

摘要全文：

Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by defective clonal hematopoiesis, bone marrow fibrosis, splenomegaly, severe anemia, and the propensity for transformation to acute myeloid leukemia (AML). Inhibitors targeting JAKs (Janus kinases) have revolutionized the treatment of MF, but are limited by modest e?cacy or acquired resistance after prolonged treatment. Here, we report a novel inhibitor, HP560 that targets BET (bromodomain and extra-terminal) proteins and shows promising therapeutic activities against MF and AML. Through engaging the bromodomain pocket of BET proteins in a competitive manner with acetylated histones, HP560 causes the disruption of BET proteins from chromatin. HP560 has high binding affinities for all BET proteins and strong anti-proliferative activity as well as synergistic anti-proliferative effect in combination with ruxolitinib, a JAK1/2 inhibitor. In an MF cell line derived tumor xenograft (CDX) mouse model, HP560 prolongs survival and improves splenomegaly and anemia, and these effects are enhanced when combined with ruxolitinib. HP560 also significantly and dose-dependently inhibits tumor growth in an AML CDX mouse model. Together, HP560 is a potent pan-BET inhibitor and can be developed as a monotherapy or in combination with a JAK inhibitor for the treatment of MF. HP560 structure will not be disclosed.

摘要標題：

Discovery of HP567, a highly potent, brain-penetrating, and H1047R-selective PI3Kα inhibitor for the treatment of tumors bearing H1047R mutation

摘要作者：

J. Li, L. Fan, C. Liu, Y. Luo, X. Chu, H. Yu, F. Wang, X. Li;

Hinova Pharmaceuticals, Chengdu Shi, China

摘要全文：

The phosphoinositide 3 kinase (PI3K)-protein kinase B (PKB/AKT) is one of the most altered pathways in human cancer and its hyperactivation promotes tumor growth and survival. H1047R increases kinase activity and is the most common PI3Kα mutation with a mutation rate of 7.8% in all cancers, and 21%, 5% and 3% in breast cancer, endometrium, and ovarian cancer, respectively. Alpelisib is an FDA approved PI3Kα inhibitor targeting both wildtype (WT) and mutant PI3Kα, yet its clinical benefit is limited by the toxicities including hyperglycemia and rash (which are considered on target effects of WT- PI3Kα inhibition). Here, we report an allosteric and brainpenetrating PI3Kα inhibitor, HP567 that is 14-fold selective for PI3Kα H1047R over PI3Kα WT and is 80-fold selective over other PI3K isoforms. HP567 strongly inhibits proliferation and p-AKT (S473) in H1047R mutant cell lines with an average IC of 138 nM and 8 nM, respectively, and has no activity against PI3Kα WT cell lines. HP567 strongly inhibits growth of tumors bearing H1047R in multiple CDX models including breast cancers (MDA-MB-453, T47D, and CAL-148), ovarian cancer (SK-OV-3), tongue squamous cell carcinoma (CAL-33), and a brain-metastatic breast cancer (MDA-MB-453), without causing hyperglycemia or increases in plasma insulin levels. In conclusion, HP567 is a novel, potent, and brain-penetrating PI3Kα H1047R selective inhibitor. The pre-clinical data supports the clinical development of HP567 for the treatment of tumors bearing PI3Kα H1047R mutations. Structure of HP567 will not be disclosed.

摘要標題：

Discovery of HC-4955, a novel AR-V7-targeting PROTAC for the treatment of mCRPC

摘要作者：

J. Li, Z. Tu, W. Du, X. Xiang, Z. Wen, Y. You, L. Zhao, Y. Chen, C. Yang, H. Yuan, X. Li;

Hinova Pharmaceuticals, Chengdu Shi, China

摘要全文：

Prostate cancer is the second most commonly diagnosed cancer and the second leading cause of cancer death among men worldwide. Androgens play an important role in the development and progression of prostate cancers and targeting androgen receptor (AR) signaling axis over decades has remained a mainstay of prostate cancer therapy. Next generation hormonal agents (NHAs) enzalutamide and abiraterone have brought clinical beneíts for metastatic castrate-resistant prostate cancer (mCRPC) patients, AR axis-targeted therapy resistance is inevitable due to AR gene ampliícation or mutations. AR-V7 is the most clinically relevant AR splice variant associated with endocrine resistance and poor prognosis. AR-V7 constitutively activates AR signaling and lacks the ligand binding domain (LBD) where hormones and AR antagonists interact, resulting in resistance to AR signaling inhibitors (ARSi). Thus, AR-V7 is a promising therapeutic target to address ARSi resistance in mCRPC. We have discovered a highly potent AR-V7 proteolysis targeting chimera (PROTAC), HC-4955 that degrades both the wild-type AR (WT-AR) and AR-V7 mutant. HC-4955 degrades AR-V7 with DC50 < 5 nM. In silico molecular docking analysis predicts the binding of HC-4955 to the N-terminal domain of AR and then the essential amino acids contributed to HC-4955 binding are validated by mutational analysis studies. HC-4955 also potently degrades mutants of AR-LBD mutations including L702H and T878A and these mutations are also associated with ARSi resistance. HC-4955 strongly inhibits proliferation of ARSi-resistant prostate cancer cell lines with IC50 < 10 nM. HC-4955 shows a robust anti-tumor activity in the AR-V7-bearing 22Rv1 cell line derived tumor xenograft (CDX) and patient-derived xenograft (PDX) mouse models, with majority of the tumors completely regressed and > 90% AR-V7 expression decreased at 1-5 mg/kg (QD, PO) in these models. The pre-clinical results support the clinical development of HC-4955 for the treatment of mCRPC. Selected pre-clinical data along with the chemical structure of HC-4955 will be presented.