KRAS-G12D(Seed Therapeutics)

2024年10月23日，和誉医药（港交所代码：02256）宣布，公司两项临床前研究结果在10月于西班牙巴塞罗那举行的第36届国际分子靶标与癌症治疗大会上发布（EORTC-NCI-AACR conference, 以下简称ENA大会）。这两项研究成果分别展示了和誉医药在研管线中潜在同类最优的PRMT5*MTA抑制剂和口服KRASG12D小分子抑制剂的最新临床前研究进展。作为全球最高质量的聚焦分子靶向与肿瘤治疗的研究会议，ENA大会聚集了肿瘤治疗领域的创新药物和创新疗法的最新进展。 和誉医药在本届EORTC-NCI-AACR大会上展示壁报如下： 标题：一款潜在同类最佳的MTA 协同 PRMT5 抑制剂ABSK131的临床前表征 摘要编号：41 壁报板号：PB029 会议时间：10月23日9:00-20:30 星期三（西班牙时间） 会议地点：壁报展厅 研究背景： 在大约10%-15%的人类肿瘤中MTAP基因呈纯合缺失状态。已经证明PRMT5*MTA抑制剂与MTAP基因缺失呈合成致死关系。一代PRMT5抑制剂因为无法区分PRMT5*MTA和PRMT5，导致在临床应用中受限于其狭窄的治疗窗口。一些选择性的PRMT5*MTA抑制剂已经进入到了临床阶段，但它们的活性和选择性还有待进一步提高。通过先进的计算辅助结构分析和药物化学设计，我们发现了一款潜在同类最佳的MTA协同PRMT5抑制剂ABSK131,该抑制剂具有更好的活性，选择性以及透过血脑屏障的能力。 结论： 和誉医药展示的ABSK131是一种高选择性的可入脑的MTA协同PRMT5抑制剂，其卓越的特性支持其快速的临床前开发。 标题：一款具有高口服利用度的KRASG12D小分子抑制剂的发现与表征 摘要编号：40 壁报板号：PB028 会议时间：10月23日9:00-20:30 星期三（西班牙时间） 会议地点：壁报展厅 研究背景： KRASG12D 突变（在12位的甘氨酸突变成了天冬氨酸）大约占到胰腺癌的35%，结直肠癌的13%和非小细胞肺癌的5%。一些已经发现的KRASG12D的抑制剂都只表现出非常有限的口服利用率。这里，我们展示了一款新型具有高口服利用度的KRASG12D小分子抑制剂ABSK141的临床前研究和表征。 结论： 在体外实验中，ABSK141展示出对于KRASG12D很高的结合能力和良好的生化活性，它还在一系列KRASG12D的肿瘤细胞系里展示出了对于KRAS下游信号通路的强烈抑制作用和高效的抗增殖能力。体内药效实验也显示出ABSK141在多个不同的KRASG12D 肿瘤模型中的强效抗肿瘤能力。临床前DMPK的分析也证明了它在不同种属中都具有极佳的生物利用度。综上，ABSK141 卓越的临床前特性为其快速地临床前开发提供了支持。 Abbisko presented preclinical research results of its PRMT5* MTA and oral KRASG12D programs at the 36th International Molecular Targets and Cancer Treatment Conference (EORTC-NCI-AACR) 23 October 2024, Shanghai—Abbisko Therapeutics Co., Ltd. (“Abbisko” hereafter) announced presentation of the results of its two preclinical programs at the 36th International Molecular Targets and Cancer Treatment Conference (EORTC) held in Barcelona, Spain. These two presentations demonstrated the latest preclinical research progress of a potential best-in-class PRMT5*MTA inhibitor and a potential best-in-class oral KRASG12D inhibitor from Abbisko pipeline. As one of the world's highest-quality oncology research conference focusing on molecular targeting and tumor treatment, the ENA conference collects the most cutting-edge researches on innovative drugs and therapies in the field of tumor treatment. Abbisko presented the following posters at the ENA conference: Title:  Preclinical characterization of ABSK131, a potential best-in-class MTA-cooperative PRMT5 inhibitor Abstract number: 41 Poster board number: PB029 Session date and time: Wednesday, 23 October 2024| 9: 00 am-8:30 pm（Spain time） Session location: Exhibition Hall Background:  MTAP is homozygous deleted in 10-15% of all human cancers. PRMT5*MTA inhibition has been shown to be synthetic lethal with MTAP deletion. First generation PRMT5 inhibitors demonstrated limited therapeutic window due to lack of selectivity between PRMT5*MTA and PRMT5 alone. Several selective PRMT5*MTA inhibitors have advanced into the clinic but their potency and selectivity remained to be further improved. Utilizing structural and computation-aided medicinal chemistry design, we have discovered a potential best-in-class MTA-cooperative PRMT5 inhibitor ABSK131 with improved potency, selectivity, and brain-penetrant ability. Conclusion： ABSK131, presented here by Abbisko Therapeutics, is a highly selective MTA-cooperative and brain-penetrant PRMT5 inhibitor. Its superior profile supports its advancement into clinical studies. Title:  Discovery and characterization of a highly orally available small molecule inhibitor of KRASG12D Abstract number: 40 Poster board number: PB028 Session date and time: Wednesday, 23 October 2024| 9: 00 am-8:30 pm（Spain time） Session location: Exhibition Hall Background:  KRASG12D mutation (single amino acid substitution of Glycine for aspartic acid at position 12), accounts for ~35% of pancreatic cancer, ~13% of colorectal cancer, and ~5% of non-small cell lung cancer. Several KRASG12D inhibitors that have been discovered appeared to carry limited oral bioavailability. Here, we describe the discovery and preclinical characterization of ABSK141, a novel, potent, and highly orally bioavailable small-molecule KRASG12D inhibitor. Conclusion： ABSK141 demonstrated high binding affinity and good biochemical activity to KRASG12D in vitro. ABSK141 also displayed strong inhibition of KRAS downstream signaling and anti-proliferation activity across a panel of KRASG12D cancer cell lines with good selectivity. Furthermore, in vivo efficacy studies showed that ABSK141 has strong anti-tumor activity in multiple KRASG12D xenograft models. Preclinical DMPK analysis demonstrated excellent bioavailability across several animal species. Together, the superior preclinical profile of ABSK141 supports its fast-track preclinical development. 关于和誉 和誉医药（香港联交所代码：02256）是一家立足中国，着眼全球的创新药研发公司。公司的创始人和管理团队拥有多年顶尖跨国药企的研发和管理经验，并参与了多个临床及上市新药的研发。和誉医药专注于肿瘤新药研发，以小分子肿瘤精准治疗和小分子肿瘤免疫治疗药物为核心，着眼病患及医药市场的需求，秉承国际新药开发的理念和标准，致力于开发新颖及高潜力药物靶点的潜在first-in-class或best-in-class创新药物，用于改善中国及全球病人的生活质量。 自2016年成立以来，和誉医药已拥有由16种候选药物组成的产品管线，涵盖肿瘤精准治疗领域以及肿瘤免疫治疗领域。 更多信息，欢迎访问 www.abbisko.com。