PO.CH01.03 · 化学

一种强效、口服生物利用度高、高选择性的小分子非共价KRAS[G12D]抑制剂的发现与临床前评估

Discovery and preclinical evaluation of a potent, orally bioavailable, highly selective, small molecule non-covalent KRAS[G12D] inhibitor

编号 5132 展板 15 时间 4/21 09:00–12:00 区域 Section 38 主讲 Alexei Pushechnikov, B Eng;M Eng;PhD

分会场 New Ligands and Inhibitors

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作者与单位 Authors & Affiliations

Alexei Pushechnikov¹, Volodymyr Kysil², Ruben Karapetian³, Stepan Mochalov⁴, Aleksei Riakhovskii⁴, Elena Bulanova⁴, Nikolay Savchuk⁵, Iain Dukes⁵

¹Expert Systems, Inc., San Diego, CA,²ChemDiv, Inc., San Diego, CA,³Expert Systems, Inc, Dover, DE,⁴Navegador Biosciences, Cantanhede, Portugal,⁵Eilean Therapeutics LLC, Philadelphia, PA

摘要 Abstract

中文摘要

KRAS[G12D]致癌突变存在于约35%的胰腺癌、13%的结直肠癌和4%的非小细胞肺癌中。该突变也发生于其他癌症类型中，尽管频率较低。在此，我们希望呈现有力证据，表明ZE98-0277在KRAS[G12D]突变细胞系和体内模型中具有强效且选择性的活性。 ZE98-0277候选药物表现出强效的体外活性（IC50 KRAS[G12D] 6.3 nM）和口服PK，在小鼠和猴中的生物利用度约为20-40%，治疗窗宽（细胞模型中>100倍），安全性和耐受性良好，ADME特性优良（溶解度、稳定性、渗透性、低hERG抑制、极小的脱靶效应），并在多个小鼠异种移植模型中有效抑制肿瘤。这些临床前结果表明，ZE98-0277是一种强效、选择性且口服生物利用度高的KRAS[G12D]抑制剂，对KRAS[G12D]突变肿瘤具有强效疗效，拟进行进一步开发。

查看英文原文 English abstract

KRAS[G12D] oncogenic mutation is present in ~35% of pancreatic, 13% of colorectal, and 4% of non-small cell lung cancers. The mutation also occurs in other cancer types, albeit less frequently. Here we would like to present compelling evidences that ZE98-0277 has potent and selective activity in KRAS[G12D] mutant cell lines and in vivo models. ZE98-0277 drug candidate demonstrates strong in vitro activity (IC50 KRAS[G12D] 6.3 nM) and oral PK, bioavailability ~20-40% in mice and monkeys, broad therapeutic window (>100x in cellular models), good safety and tolerability, favorable ADME properties (solubility, stability, permeability, low hERG inhibition, minimal off-target effects), effective tumor suppression in multiple mouse xenograft models. These preclinical results demonstrate that ZE98-0277 is a potent, selective, and orally bioavailable KRAS[G12D] inhibitor, strongly efficacious against KRAS[G12D] mutant tumors slated for further development.

利益披露 Disclosure

A. Pushechnikov, None.. V. Kysil, None.. R. Karapetian, None.. S. Mochalov, None.. A. Riakhovskii, None.. E. Bulanova, None.. N. Savchuk, None.. I. Dukes, None.

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