PO.ET09.06 · 实验与分子治疗

CGT1263 的表征:一种对突变型 KRAS 具有选择性(优于 HRAS 和 NRAS)的 KRAS(ON/OFF)抑制剂临床候选药物

Characterization of CGT1263, a KRAS (ON/OFF) inhibitor clinical candidate with selectivity for mutant KRAS over HRAS and NRAS

编号 410 展板 13 时间 4/19 02:00–05:00 区域 Section 17 主讲 John Fischer

分会场 Novel Antitumor Agents 1

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作者与单位 Authors & Affiliations

John Fischer, Kim Alley, Karyn Bouhana, Richard Brizendine, Paul Carlson, Mark Chicarelli, Michelle Crow, Brad Fell, Jennifer Fulton, Anna Guarnieri, Jackie Harrison, Ravi Jalluri, Amber Johnson, Keith Koch, Cori Malinky, Macedonio J. Mejia, Brad Newhouse, Scott Niman, Rob Rieger, John Robinson, Mareli Rodriguez, Leah Salituro, Vinny Scarato, Aaron Smith, Francis Sullivan, Yang Wang, Shannon Winski, Silas Wood, Yeyun Zhou

Cogent Biosciences, Inc, Boulder, CO

摘要 Abstract

中文摘要

致癌性 KRAS 突变发生于多种癌症类型,包括胰腺癌、肺癌和结直肠恶性肿瘤。虽然等位基因特异性 KRAS 抑制剂已在患者中显示出临床获益,但大多数 KRAS 突变型癌症仍缺乏有效疗法。近期为解决这一差距所做的努力促成了对靶向临床相关突变和改变的泛 KRAS 抑制剂的鉴定。在此,我们重点介绍临床候选药物 CGT1263,一种新型泛 KRAS 抑制剂,它同时结合 KRAS 的活性(ON)和非活性(OFF)状态,同时不抑制 HRAS 和 NRAS。CGT1263 在一组 KRAS 改变细胞系的肿瘤球体测试中展现出强大的抗增殖活性。对 CGT1263 前药 CGT1815 的体内表征包括跨物种的稳态药代动力学、药效学以及在 KRAS 改变的小鼠肿瘤模型中的疗效。

查看英文原文 English abstract

Oncogenic KRAS mutations occur across multiple cancer types, including pancreatic, lung, and colorectal malignancies. While allele-specific KRAS inhibitors have demonstrated clinical benefit in patients, the majority of KRAS mutant cancers remain without effective therapies. Recent efforts to address this disparity have resulted in the identification of pan KRAS inhibitors that target clinically relevant mutations and alterations. Herein, we highlight the clinical candidate CGT1263, a novel pan KRAS inhibitor that engages both the active (ON) and inactive (OFF) states of KRAS while sparing HRAS and NRAS inhibition. CGT1263 demonstrates robust anti-proliferative activity across a tumor spheroid panel of KRAS altered cell lines. In vivo characterization of CGT1815, the prodrug of CGT1263, includes steady state pharmacokinetics across species, pharmacodynamics, and efficacy in KRAS altered mouse tumor models.

利益披露 Disclosure

J. Fischer, Cogent Biosciences, Inc. Employment, Stock, Stock Option. K. Alley, Cogent Biosciences, Inc. Employment, Stock, Stock Option. K. Bouhana, Cogent Biosciences, Inc. Employment, Stock, Stock Option. R. Brizendine, Cogent Biosciences, Inc. Employment, Stock, Stock Option. P. Carlson, Cogent Biosciences, Inc. Employment, Stock, Stock Option. M. Chicarelli, Cogent Biosciences, Inc. Employment, Stock, Stock Option. M. Crow, Cogent Biosciences, Inc. Employment, Stock, Stock Option. B. Fell, Cogent Biosciences, Inc. Employment, Stock, Stock Option. J. Fulton, Cogent Biosciences, Inc. Employment, Stock, Stock Option. A. Guarnieri, Cogent Biosciences, Inc. Employment, Stock, Stock Option. J. Harrison, Cogent Biosciences, Inc. Employment, Stock, Stock Option. R. Jalluri, Cogent Biosciences, Inc. Employment, Stock, Stock Option. A. Johnson, Cogent Biosciences, Inc. Employment, Stock, Stock Option. K. Koch, Cogent Biosciences, Inc. Employment, Stock, Stock Option. C. Malinky, Cogent Biosciences, Inc. Employment, Stock, Stock Option. M. J. Mejia, Cogent Biosciences, Inc. Employment, Stock, Stock Option. B. Newhouse, Cogent Biosciences, Inc. Employment, Stock, Stock Option. S. Niman, Cogent Biosciences, Inc. Employment, Stock, Stock Option. R. Rieger, Cogent Biosciences, Inc. Employment, Stock, Stock Option. J. Robinson, Cogent Biosciences, Inc. Employment, Stock, Stock Option. M. Rodriguez, Cogent Biosciences, Inc. Employment, Stock, Stock Option. L. Salituro, Cogent Biosciences, Inc. Employment, Stock, Stock Option. V. Scarato, Cogent Biosciences, Inc. Employment, Stock, Stock Option. A. Smith, Cogent Biosciences, Inc. Employment, Stock, Stock Option. F. Sullivan, Cogent Biosciences, Inc. Employment, Stock, Stock Option. Y. Wang, Cogent Biosciences, Inc. Employment, Stock, Stock Option. S. Winski, Cogent Biosciences, Inc. Employment, Stock, Stock Option. S. Wood, Cogent Biosciences, Inc. Employment, Stock, Stock Option. Y. Zhou, Cogent Biosciences, Inc. Employment, Stock, Stock Option.

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