Mcl-1

ROCKVILLE, Md. and SUZHOU, China, April 7, 2024 /PRNewswire/ -- Ascentage Pharma (6855.HK), a global biopharmaceutical company engaged in developing novel therapies for cancer, age-related diseases, and chronic hepatitis B (CHB), announced today that it releases the latest results from three preclinical studies of its novel drug candidates olverembatinib, MDM2-p53 inhibitor alrizomadlin (R&D Code: APG-115), FAK/ALK/ROS1 tyrosine kinase inhibitor APG-2449, and embryonic ectoderm development (EED) inhibitor APG-5918, at the 2024 American Association of Cancer Research Annual Meeting (AACR 2024). This year's AACR annual meeting will be held from April 5-10 2024, in San Diego, California, USA. "We are pleased to present the preclinical research data of four assets in our pipeline at the AACR 2024. The results provided essential support for the potential clinical development and therapeutic combinations of these compounds in SDH-deficient neoplasms, prostate cancer, and ovarian cancer," said Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma. "Moving forward, we will continue to advance these programs toward the clinical stage in order to bring more treatment options to patients in need." The details of these three preclinical studies are as follows: Olverembatinib, a novel multikinase inhibitor, demonstrates superior antitumor activity in succinate dehydrogenase (SDH)-deficient neoplasms Abstract#: 1971 Time: Monday April 8, 2024, 9:00 AM - 12:30 PM (Pacific Time) Introduction: Succinate dehydrogenase (SDH) – deficient (dSDH) neoplasms are identified by the loss of immunohistochemical expression of SDHB due to the bi-allelic inactivation of any of the four components of mitochondrial SDH complex (SDH A-D). Succinate accumulation, due to SDH deficiency, is involved in tumorigenesis of different types of cancers including gastrointestinal stromal tumor (GIST), paraganglioma, pheochromocytoma, renal cell carcinoma, pituitary adenomas, and pancreatic neuroendocrine tumors. The prognosis of patients with dSDH neoplasia, especially GIST, is poor and approved tyrosine kinase inhibitors (TKIs) have limited efficacy. There is a high unmet medical need for these patients. Olverembatinib, a novel multi-kinase inhibitor, targets a broad spectrum of kinases and has demonstrated promising efficacy in dSDH GIST patients in an ongoing phase I clinical trial. In this study, we assessed antitumor effects of olverembatinib in preclinical models of dSDH cancers and dSDH GIST primary tumor cells, and explored potential mechanisms of action. Conclusions: Olverembatinib showed superior anti-tumor activity in dSDH cell lines in vitro and human dSDH GIST primary tumor cells ex vivo. Olverembatinib, as a multi-target kinase inhibitor, exerted antitumor effects by modulating multiple signaling pathways including hypoxia, angiogenesis, apoptosis, proliferation, and survival, which are involved in tumorigenesis of dSDH cancers. Olverembatinib demonstrated more potent in vivo antitumor activity in mice bearing PC12#5F7 (SDHB KD) xenograft tumors than other TKIs. Western blot analysis in tumor tissues collected from mice further confirmed the modulation of the signal pathways by olverembatinib observed in cell lines. In summary, the results provide a rationale for future clinical development of olverembatinib in dSDH cancers. Embryonic ectoderm development (EED) inhibitor APG-5918 (EEDi-5273) and MDM2 inhibitor alrizomadlin (APG-115) synergistically inhibit tumor growth in preclinical models of prostate cancer (PCa) Abstract#: 3223 Time: Monday April 8, 2024, 1:30 PM - 5:00 PM (Pacific Time) Introduction: Prostate cancer (PCa) is one of the most frequently diagnosed malignancies among elderly males. Androgen deprivation therapy (ADT) with or without androgen receptor (AR) inhibitors is widely used as initial treatment for advanced PCa. However, most ADT-treated patients eventually develop castration-resistant prostate cancer (CRPC), which is in urgent need of novel therapies. Polycomb repressive complexes 2 (PRC2) dysregulation is common in PCa and correlates with poor prognosis. PRC2 mediates histone H3 lysine 27 tri-methylation (H3K27me3), a repressive epigenetic marker for gene transcription. embryonic ectoderm development (EED), a PRC2 core component, is crucial for histone methyltransferase activity through direct binding to H3K27me3. MDM2, a negative regulator of the tumor suppressor p53, is frequently amplified or overexpressed in PCa, and associated with poor clinical outcomes and metastasis. The aim of this study was to evaluate antitumor activity and molecular mechanisms of the investigational, clinical-stage EED inhibitor APG-5918/EEDi-5273 and MDM2 selective inhibitor alrizomadlin (APG-115) in PCa preclinical models Conclusions: In PCa preclinical models, the combination of APG-5918 and alrizomadlin synergistically inhibited cellular proliferation and induced cellular apoptosis. APG-5918 in combination with alrizomadlin synergistically enhanced antitumor activity in PCa xenograft models in vivo. Mechanistically, PD analysis revealed that APG-5918 downregulated the oncogenic DNA methylation factors (UHRF1, DNMT1) and histone methylation marker H3K27me3. Alrizomadlin markedly downregulated UHRF1 and DNMT1, and upregulated p53 and p21 expression. Combined treatment further enhanced downregulation of DNMT1, UHRF1, cell cycle pathway proteins (pRb, CDK6), antiapoptotic protein MCL-1, and synergistically increased cleavage of PARP-1, a marker of apoptosis. Therefore, the findings provide a scientific rationale for future clinical development of APG-5918 and alrizomadlin to treat patients with PCa. APG-2449, a novel focal adhesion kinase (FAK) inhibitor, inhibits metastasis and enhances the antitumor efficacy of PEGylated liposome doxorubicin (PLD) in epithelial ovarian cancer (EOC) Abstract#: 4569 Time: Tuesday April 9, 2024, 9:00 AM - 12:30 PM (Pacific Time) Introduction: Ovarian cancer is among the leading causes of cancer-related death in women, and most cases are diagnosed at later stages with distant metastasis. FAK overexpression or activation occurs in a substantial proportion of epithelial ovarian cancers (EOCs) and is predictive of poor clinical outcomes. FAK plays an important role in cell migration and chemoresistance, rendering FAK inhibition a promising treatment approach to reduce metastasis of tumor cells and sensitize them to chemotherapy. FAK is therefore emerging as a potential treatment target. The aim of this study was to evaluate the antitumor efficacy of investigational APG-2449, a novel FAK inhibitor, combined with PLD, a commonly used chemotherapy, in relapsed or refractory ovarian cancer. Conclusions: APG-2449 combined with doxorubicin showed synergistic antiproliferative effects in both platinum-resistant and platinum-sensitive ovarian cancer cell lines. FAK inhibition via APG-2449 alone attenuated migration of ovarian cancer cells in a dose-dependent manner. APG-2449 in combination with PLD showed enhanced antitumor activity in platinum-resistant OVCAR-3 ovarian cancer CDX model. The combination regimen prolonged ascites-free and survival times in the ID8-Luc peritoneal syngeneic model. These promising results support the future clinical development of this combination treatment for ovarian cancer. About Ascentage Pharma Ascentage Pharma (6855.HK) is a globally focused biopharmaceutical company engaged in developing novel therapies for cancers, chronic hepatitis B, and age-related diseases. On October 28, 2019, Ascentage Pharma was listed on the Main Board of the Stock Exchange of Hong Kong Limited with the stock code 6855.HK. Ascentage Pharma focuses on developing therapeutics that inhibit protein-protein interactions to restore apoptosis, or programmed cell death. The company has built a pipeline of 9 clinical drug candidates, including novel, highly potent Bcl-2, and dual Bcl-2/Bcl-xL inhibitors, as well as candidates aimed at IAP and MDM2-p53 pathways, and next-generation tyrosine kinase inhibitors (TKIs). Ascentage Pharma is also the only company in the world with active clinical programs targeting all three known classes of key apoptosis regulators. The company is conducting more than 40 Phase I/II clinical trials in the US, Australia, Europe, and China. Ascentage Pharma has been designated for multiple Major National R&D Projects, including five Major New Drug Projects, one New Drug Incubator status, four Innovative Drug Programs, and one Major Project for the Prevention and Treatment of Infectious Diseases. Olverembatinib, the company's core drug candidate developed for the treatment of drug-resistant chronic myeloid leukemia (CML) and the company's first approved product, has been granted Priority Review Designations and Breakthrough Therapy Designations by the Center for Drug Evaluation (CDE) of China National Medical Products Administration (NMPA). To date, the drug had been included into the China 2022 National Reimbursement Drug List (NRDL). Furthermore, olverembatinib has been granted an Orphan Drug Designation (ODD) and a Fast Track Designation (FTD) by the US FDA, and an Orphan Designation by the EMA of the EU. To date, Ascentage Pharma has obtained a total of 16 ODDs from the US FDA and 1 Orphan Designation from the EMA of the EU for 4 of the company's investigational drug candidates. Leveraging its robust R&D capabilities, Ascentage Pharma has built a portfolio of global intellectual property rights and entered into global partnerships with numerous renowned biotechnology and pharmaceutical companies and research institutes such as UNITY Biotechnology, MD Anderson Cancer Center, Mayo Clinic, Dana-Farber Cancer Institute, MSD, and AstraZeneca. The company has built a talented team with global experience in the discovery and development of innovative drugs and is setting up its world-class commercial manufacturing and Sales & Marketing teams. One pivotal aim of Ascentage Pharma is to continuously strengthen its R&D capabilities and accelerate its clinical development programs, in order to fulfil its mission of addressing unmet clinical needs in China and around the world for the benefit of more patients. Forward-Looking Statements The forward-looking statements made in this article relate only to the events or information as of the date on which the statements are made in this article. Except as required by law, Ascentage Pharma undertakes no obligation to update or revise publicly any forward-looking statements, whether as a result of new information, future events, or otherwise, after the date on which the statements are made or to reflect the occurrence of unanticipated events. You should read this article completely and with the understanding that our actual future results or performance may be materially different from what we expect. In this article, statements of, or references to, our intentions or those of any of our Directors or our Company are made as of the date of this article. Any of these intentions may alter in light of future development. SOURCE Ascentage Pharma

近日，由美国德克萨斯大学圣安东尼奥健康科学中心生物化学与结构生物学系和格里希儿童癌症研究所的研究团队在Nature Communications期刊发表了题为“Development and crystal structures of a potent second-generation dual degrader of BCL-2 and BCL-xL”的文章。该研究基于前期工作开发了针对BCL-2和BCL-xL的第二代双降解剂，并解析了相关的分子机制。BCL-2蛋白家族的成员是细胞凋亡的关键调节因子，包括抗凋亡（BCL-2、BCL-xL、MCL-1等）和促凋亡（BAD、BIM、PUMA、BAK、BAX等）蛋白。抗凋亡蛋白和促凋亡蛋白的相对丰度控制着细胞命运并维持体内平衡。在肿瘤发生过程中，癌细胞通过过表达抗凋亡蛋白来逃避细胞凋亡，从而帮助肿瘤发生、进展和耐药性的发展。因此，作为癌症治疗的策略，人们一直关注开发针对BCL2蛋白家族的小分子抑制剂和降解剂。2021年该团队在Nature Communications发表了针对BCL-xL和BCL-2的双降解剂753b，但该PROTAC涉及的特异性分子机制仍然未知。在这项研究中，作者确定了753b介导BCL-xL/BCL-2靶向降解的分子基础，并解析了VHL/753b/BCL-xL和VHL/753b/BCL-2三元配合物的晶体结构。而且作者发现这两种三元复合物表现出明显不同的结构，在VHL/753b连接子/靶标界面上展现不同的相互作用网络。更进一步，作者基于结构开发出了降解BCL-xL/BCL-2更强效力的降解子WH244，并解析了VHL/WH244/BCL-2的晶体结构和阐明了其提高有效性的潜在机制。首先，为最大限度地提高获得衍射质量晶体的概率，作者优化了一种获得纯三元配合物的生化复溶策略，将蛋白质和753b混合物使用凝胶过滤柱进一步纯化，对均相三元配合峰进行汇集、浓缩和结晶试验。经过大量优化，获得了VCB/753b/BCL-2（以下简称BCL-2753b）和VCB/753b/BCL-xL（以下简称BCL-xL753b）的三元配合物结构。最终的BCL-2753b和BCLxL753b结构在2.56 Å和2.94 Å分辨率下分离，R/Rfree值分别为0.20/0.25和0.20/0.24（图1）。图1其次，作者通过晶体结构发现了753b连接BCL-2和VHL的重要氨基酸残基，并通过生化测定发现将重要的氨基酸位点突变会破坏三元复合物，导致BCL-2完全缺乏多泛素链形成。但令人惊讶的是，BCL-xL753b中的BCL-xL与BCL-2753b中的BCL-2相比具有截然不同的结晶构像。来自BCL-xL753b和BCL-2753b结构的VHL亚基的叠加表明，由于PROTAC的路径改变，BCL-xL和BCL-2相对于彼此旋转近180°，并伴有~14 Å的平移。与BCL-2753b复合物不同，BCL-xL不与VHL配体相互作用（图2）。图2接着，基于BCL-xL/2与753b的两个三元复合结构，作者用更刚性的1,4-二甲基哌嗪取代了753b的柔性烷基链，进一步开发了新的PROTAC，WH244，而刚性连接子将保持复合物的整体三级排列结构，以有效地降解BCL-xL和BCL-2。通过一系列实验评估，与753b相比，WH244表现出更高的效力。此外，WH244介导的BCL-xL和BCL-2的蛋白水解具有时间依赖性，而且确认BCL-xL/BCL-2的蛋白水解是通过蛋白酶体UPS介导的。作者还评估了WH244的抗肿瘤功效，在Jurkat细胞中WH244表现出优于753b、DT2216和ABT263的效力（图3）。图3为了评估WH244和753b诱导的BCL-xL和BCL-2的降解效率，作者还通过CRISPR Cas9技术生成了内源性HiBiT敲入BCL-xL和HiBiT敲入BCL-2的HeLa细胞。进一步在编辑的细胞中进行了时间过程测定，确认WH244诱导的BCL-xL和BCL-2降解速度快于753b。为进一步评估753b和WH244对BCL-xL/BCL-2蛋白的细胞选择性，作者进行了多重串联质谱（TMT）标记质谱蛋白质组学实验和不同的蛋白质组学分析技术（即数据独立采集（DIA）蛋白质组学方法）来表征BCL-xL和BCL-2双PROTAC的靶向和脱靶效应，发现753b和WH244都显示出降解BCL-xL和BCL-2的能力，其中WH244在降解这两种蛋白质方面表现出卓越的功效。作者最后通过AlphaLISA和NanoBRET进行了体外三元复合物形成测定，观察到与753b相比，BCL-xL和BCL-2都与WH244形成了更紧密的复合物（图4）。图4最后为深入研究WH244的分子机理，作者尝试了共结晶WH244介导的三元配合物，并获得了VCB/WH244/BCL-2（以下简称BCL2WH244）的复合物衍射晶体。将BCL-2WH244结构细化为2.98 Å分辨率，R/Rfree值为0.23/0.29。作者还采用多泛素链形成测定法发现了BCL2的重要氨基酸残基位点（图5）。而且作者还分析了BCL-2WH244三元复合物与BCL-xL753b和BCL-2753b的差异，发现BCL-2在BCL2WH244中的取向相对于BCL-2753b结构中的取向完全改变，而是与BCL-xL753b结构中的BCL-xL相似。总的来说，作者认为WH244的功效增强可归因于极性1,4-二甲基哌嗪接头的整合和在BCLxL/BCL-2配体中使用桥接吗啉，这种整合导致了更稳健的二元复合物，因此BCL2WH244的三元复合物也明显更强。图5本文作者：BC声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号   粉丝群/投稿/授权/广告等请联系公众号助手 觉得本文好看，请点这里↓

SOLANA BEACH, Calif. and REDWOOD CITY, Calif., April 04, 2024 (GLOBE NEWSWIRE) -- eFFECTOR Therapeutics, Inc. (NASDAQ: EFTR), a leader in the development of selective translation regulator inhibitors (STRIs) for the treatment of cancer, today announced topline results from the primary analysis of the randomized Phase 2 KICKSTART trial which tested tomivosertib or placebo, each combined with pembrolizumab, as frontline treatment for patients with non-small cell lung cancer (NSCLC) with PD-L1 ≥50%. Based on 36 events, the hazard ratio for progression free survival (PFS, the primary endpoint of the study) using a stratified Cox proportional hazards model was 0.62 (95% confidence intervals 0.3 to 1.3) in favor of tomivosertib. The two-sided p value for PFS, based on a stratified log rank test, was 0.21, which did not meet the pre-specified threshold of p≤0.2. The median PFS was 13.0 weeks in the tomivosertib plus pembrolizumab arm and 11.7 weeks in the placebo plus pembrolizumab arm, respectively. Overall survival results remain immature, however no trend favoring tomivosertib was observed. There were 67% Grade 3 or higher treatment emergent adverse events in the tomivosertib plus pembrolizumab arm versus 37% in the placebo plus pembrolizumab arm. “While there was evidence of modest tomivosertib activity in the trial, based on the totality of the data currently available we do not see an obvious path forward to continue developing tomivosertib in frontline NSCLC,” said Steve Worland, Ph.D., president and chief executive officer of eFFECTOR. “We sincerely appreciate the contributions of all the patients, their families, and trial site professionals who contributed to the execution of the trial. We will continue to analyze trial data and hope to present our findings at a future medical conference.” Dr. Worland continued: “While we’re disappointed that tomivosertib won’t be moving forward in frontline NSCLC, our strategy to maximize the value of all assets in our pipeline remains unchanged. Zotatifin, with its novel mechanism distinct from that of tomivosertib’s, is a drug candidate that is poised to enter a randomized, potentially registrational trial in estrogen receptor positive (ER+) breast cancer later this year. Our focus is now further sharpened towards advancing zotatifin through development as efficiently as possible, building on the recent positive updates of median PFS (mPFS) and safety data at last year’s San Antonio Breast Cancer Symposium (SABCS®). As a next step for the zotatifin program, we expect to report additional data, including the recommended phase 2 dose (RP2D), for zotatifin combined with fulvestrant and abemaciclib in the second half of 2024. In addition, as part of our strategy to leverage investigator-sponsored trials to conserve capital, a separate, investigator-sponsored trial of tomivosertib in acute myeloid leukemia (AML) will continue unchanged. The mechanistic rationale to test tomivosertib in AML is entirely distinct from the rationale in NSCLC and relies on tomivosertib’s potential to inhibit production of survival proteins Mcl-1 and Bcl-2, which are required for leukemia cell survival.” About eFFECTOR Therapeutics eFFECTOR is a clinical-stage biopharmaceutical company pioneering the development of a new class of oncology drugs referred to as STRIs. eFFECTOR’s STRI product candidates target the eIF4F complex and its activating kinase, mitogen-activated protein kinase interacting kinase (MNK). The eIF4F complex is a central node where two of the most frequently mutated signaling pathways in cancer, the PI3K-AKT and RAS-MEK pathways, converge to activate the translation of select mRNA into proteins that are frequent culprits in key disease-driving processes. Each of eFFECTOR’s product candidates is designed to act on a single protein that drives the expression of a network of functionally related proteins, including oncoproteins and immunosuppressive proteins in T cells, that together control tumor growth, survival and immune evasion. Zotatifin, eFFECTOR’s inhibitor of eIF4A, is currently being evaluated in a Phase 2a expansion cohort in combination with fulvestrant and abemaciclib in ER+ breast cancer. Tomivosertib, eFFECTOR’s MNK inhibitor, is currently being evaluated in an investigator-sponsored trial in AML. eFFECTOR has a global collaboration with Pfizer to develop inhibitors of a third target, eIF4E. Forward-Looking StatementseFFECTOR cautions you that statements contained in this press release regarding matters that are not historical facts are forward-looking statements. The forward-looking statements are based on our current beliefs and expectations and include, but are not limited to: the potential therapeutic benefits of our product candidates; our plans to focus our development efforts on, and advance the development of, zotatifin in ER+ breast cancer, including the potential for additional data, determination of an RP2D and to enter a registrational trial, the timing thereof; our expectations for the continuation of the investigator initiated study of tomivosertib in AML; our strategy to maximize the value of all assets in our pipeline; and our plans regarding the presentation of data findings at a future medical conference. Actual results may differ from those set forth in this press release due to the risks and uncertainties inherent in our business, including, without limitation: interim results previously reported for the zotatifin clinical trial are not necessarily indicative of final results and one or more of the clinical outcomes may materially change as patient enrollment continues, following more comprehensive reviews of the data and as more patient data becomes available, including the risk that unconfirmed responses may not ultimately result in confirmed responses to treatment after follow-up evaluations; topline results that we report is based on a preliminary analysis of key efficacy and safety data, and such data may change following a more comprehensive review of the data related to the clinical trial and such topline data may not accurately reflect the complete results of a clinical trial; we may be unable to identify a path forward for zotatifin or tomivosertib based on our limited capital resources, which we may use sooner than expected and may be insufficient to allow clinical trial readouts or further clinical development or for us to continue our operations; our lender may seek to declare a default under our loan and security agreement to the extent that a material adverse change in our business is deemed to have occurred or otherwise and accelerate immediate repayment of all outstanding obligations under our loan agreement; our dependence on third parties in connection with product manufacturing, research and preclinical and clinical testing; the results of preclinical studies and early clinical trials are not necessarily predictive of future results; the success of our clinical trials and preclinical studies for our product candidates is uncertain; regulatory developments in the United States and foreign countries; unexpected adverse side effects or inadequate efficacy of our product candidates that may limit their development, regulatory approval and/or commercialization, or may result in recalls or product liability claims; and other risks described in our prior filings with the Securities and Exchange Commission. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof, and we undertake no obligation to update such statements to reflect events that occur or circumstances that exist after the date hereof. All forward-looking statements are qualified in their entirety by this cautionary statement, which is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Contacts: Investors: Media:Christopher M. CalabreseManaging DirectorLifeSci Advisors917-680-5608ccalabrese@lifesciadvisors.comKevin GardnerManaging DirectorLifeSci Advisors617-283-2856kgardner@lifesciadvisors.comMike TattoryAccount SupervisorLifeSci Communications609-802-6265mtattory@lifescicomms.com