PRMT5-MTA inhibitors (Schrödinger)

New preclinical data on PRMT5-MTA inhibitor program will also be presented NEW YORK, NY, USA I October 23, 2024 I Schrödinger (Nasdaq: SDGR) today announced new preclinical data on SGR-3515, its investigational Wee1/Myt1 inhibitor, during a poster session at the 36th EORTC-NCI-AACR Symposium (ENA 2024). The data demonstrate that in preclinical models, treatment with SGR-3515 results in synergistic anti-tumor activity that leads to deeper and more durable responses compared to inhibitors that target only Wee1 or Myt1. The preclinical data also show that SGR-3515 has a favorable pharmacological profile and dosing schedule that supports evaluating intermittent dosing in patients. Wee1 and Myt1 kinases regulate the cell cycle and DNA damage response, allowing time for DNA repair before cell division takes place. Concurrent loss of function or inhibition of Wee1 and Myt1 confers selective vulnerability in cancer cells, a mechanism referred to as synthetic lethality, which has become an emerging therapeutic strategy for a range of cancers. A Phase 1 dose-escalation study of SGR-3515 in patients with advanced solid tumors is ongoing in the U.S. and Canada, and initial data from the clinical study is expected in the second half of 2025. Schrödinger will also present preclinical data from its PRMT5-MTA program during a poster session on October 25. Schrödinger scientists have identified a novel series of selective, potent PRMT5-MTA inhibitors and are optimizing lead compounds for use in peripheral and brain tumors. “We are pleased to share these encouraging preclinical data on SGR-3515, a potential best-in-class treatment for patients with a broad range of solid tumors, including uterine and ovarian cancers, two patient populations with high unmet need,” stated Karen Akinsanya, Ph.D., president of R&D therapeutics at Schrödinger. “We also look forward to presenting preclinical data on the discovery of a novel series of compounds for our PRMT5-MTA inhibitor program. These programs highlight how we are deploying our computational platform at scale to discover highly optimized molecules to address diseases with significant medical need, and we believe the future of our therapeutics portfolio is very promising.” SGR-3515 Data at ENA 2024 The presentation (Abstract # 147), “Discovery of SGR-3515, a first-in-class Wee1/Myt1 inhibitor with differentiated pharmacological properties in xenograft tumor models,” includes preclinical data demonstrating superior anti-tumor activity of SGR-3515 compared to inhibitors of Wee1 or Myt1 alone due to strong target engagement of both Wee1 and Myt1. The data show that SGR-3515 is a more potent co-inhibitor of both Wee1 and Myt1 than previously disclosed inhibitors of either target. These data are consistent with prior preclinical observations demonstrating that SGR-3515 has a unique and differentiated pharmacological profile that supports evaluating an intermittent dosing schedule of three days on and 11 days off, as well as five days on and nine days off, which maintained anti-tumor activity while allowing recovery from any mechanism-based hematological toxicity in preclinical models. The preclinical data also demonstrate superior kinase selectivity and in vitro cell potency of SGR-3515 across a broad cell line panel compared to other known Wee1 and Myt1 inhibitors. These new data suggest that SGR-3515 is significantly more selective than existing compounds with low potential for drug-drug interaction. PRMT5-MTA Data at ENA 2024 Additionally, Schrödinger will present new preclinical data on its PRMT5-MTA inhibitor program at a poster session during the meeting on October 25 from 9:00 a.m. – 3:00 p.m. CEST. The presentation (Abstract # 372), “Discovery of a highly MTA-synergistic series of PRMT5 inhibitors for the treatment of MTAP-deficient tumors by virtual screening technology,” will include preclinical data on the discovery of highly selective PRMT5-MTA inhibitors. The poster will describe how Schrödinger’s virtual screening platform facilitated the identification of structurally distinct chemical matter with a high degree of MTA-synergy for compounds within a novel chemical series in vitro and in cellular contexts. Schrödinger has identified a novel series of selective, potent PRMT5-MTA inhibitors that did not show major off-target liabilities such as hERG inhibition in preclinical studies and may be suitable for use in combinations across tumor types. About Schrödinger Schrödinger is transforming the way therapeutics and materials are discovered. Schrödinger has pioneered a physics-based computational platform that enables discovery of high-quality, novel molecules for drug development and materials applications more rapidly and at lower cost compared to traditional methods. The computational platform is licensed by biopharmaceutical and industrial companies, academic institutions, and government laboratories around the world. Schrödinger’s multidisciplinary drug discovery team also leverages the software platform to advance a portfolio of collaborative and proprietary programs to address unmet medical needs. Founded in 1990, Schrödinger has approximately 850 employees and is engaged with customers and collaborators in more than 70 countries. To learn more, visit www.schrodinger.com , follow us on LinkedIn , or visit our blog, Extrapolations.com . SOURCE: Schrödinger

湃隆生物二代PRMT5抑制剂 GTA182的IND申请获NMPA批准 用于治疗MTAP缺失的肿瘤 ·  潜在的best-in-class MTA协同PRMT5抑制剂 ·  在MTAP缺失的胶质母细胞瘤及非中枢神经系统肿瘤的临床前模型中，展示了显著扩大的治疗窗口。 ·  湃隆生物计划于2025年向美国FDA提交GTA182的IND申请 2024年10月14日，美国加州旧金山和中国上海 今天，湃隆生物（Apeiron Therapeutics），一家利用前沿技术与人工智能进行精准肿瘤治疗药物研发的生物制药公司，宣布成功获得中国国家药品监督管理局（NMPA）关于GTA182的临床试验申请（IND）的批准。GTA182是一种潜在的best-in-class MTA协同PRMT5抑制剂，用于治疗MTAP缺失的实体瘤。 MTAP（甲硫腺苷磷酸化酶）与抑癌基因CDKN2A在10%-15%的各类肿瘤患者中共同缺失。GTA182是一种二代MTA协同、具有透脑性的蛋白精氨酸甲基转移酶5（PRMT5）抑制剂，已在临床前研究中展示出显著扩大的治疗窗口。 “NMPA批准GTA182的IND申请是湃隆生物的一个重要里程碑。”湃隆生物联合创始人兼高级副总裁Fred Aswad博士表示。“GTA182代表了针对MTAP缺失肿瘤的重大研究进展。我们的临床前数据表明，其在多个模型中，包括极具挑战性的胶质母细胞瘤（GBM）中，展现了显著的肿瘤抑制和缩小效果。我们非常期待将这一疗法推进至临床试验，并计划于2025年向美国FDA提交IND申请，以推动我们的全球开发计划。” GTA182的一期临床试验为开放标签、多中心研究，分为剂量递增和剂量扩展两个阶段。该研究将招募MTAP缺失实体瘤患者，主要目标为评估GTA182的安全性和耐受性，并确定其最佳治疗剂量。 关于GTA182 GTA182是湃隆生物通过其人工智能指导药物发现平台自主研发的小分子化合物，在临床前研究中，湃隆生物证明了GTA182是一种高效且高选择性的PRMT5抑制剂，对MTAP缺失肿瘤细胞株具有超过100倍的选择性。重要的是，GTA182具有透脑性，并在体内临床前模型中显示出对肿瘤生长的抑制和缩小作用，包括胶质母细胞瘤（GBM）以及多种MTAP缺失的非中枢神经系统癌症模型。 关于湃隆生物 湃隆生物以全新的方式重新定义医学发现，利用人工智能优化药物研发的全过程—从靶点选择到临床试验。凭借位于旧金山湾区和上海的两大战略研发中心，湃隆生物成功整合了跨越多个地区的顶尖人才和尖端技术。我们坚信，通过持续推动生物医学创新的边界、吸引全球优秀人才，湃隆生物能够为高度未满足的医疗需求提供突破性药物。 来源 | 湃隆生物