PO.CH01.01 · 化学
设计与合成靶向携带KRAS G12D、G12V和G12C突变癌症的高效CRBN基pan-KRAS降解剂
Design and synthesis of highly efficacious CRBN-based pan-KRAS degraders targeting cancers with KRAS G12D, G12V and G12C mutations
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
KRAS的致癌突变是最有前景的癌症靶点之一。使用抑制剂治疗不可避免地导致耐药迅速出现,并在数月后丧失治疗效果。KRAS PROTACs可能通过消除突变蛋白、破坏支架功能并激活免疫应答而提供更优的疗效,从而克服耐药的快速产生。使用我们内部开发的新型E3配体,我们的化合物在携带G12D、G12V和G12C突变的细胞系体外检测中实现了低于1 nM的DC50和IC50。它们在小鼠中展现出优异的药代动力学和药效学特性,在大鼠、犬和猴中具有出色的药代动力学。在10 mg/kg、每周一次(qW)剂量下,化合物在SW620异种移植瘤(KRAS G12V突变的稳健且具挑战性的模型)中实现了超过92%的显著肿瘤生长抑制(TGI)。此外,在一项使用携带SW1990异种移植瘤小鼠的疗效研究中,在10 mg/kg、每周一次(qW)剂量下,化合物使肿瘤消退超过90%。
查看英文原文 English abstract
Oncogenic mutation of KRAS is one of the most promising targets for cancer. Treatment with inhibitors inevitably lead to rapid onset of resistance, and loss of therapeutic effect after months. KRAS PROTACs may offer superior efficacy by eliminating mutated protein, disrupting scaffolding function and activating immune response, thus overcoming the rapid development of resistance. Using new E3 ligands developed in house, our compounds achieved less than 1 nM DC 50 and IC 50 in in vitro assays with G12D, G12V and G12C mutated cell lines. They exhibited excellent pharmacokinetic and pharmacodynamic properties in mice, and outstanding pharmacokinetic in rats, dogs, and monkeys. At 10 mg/kg, qW, the compounds achieved a remarkable TGI of over 92% in SW620 xenograft, a robust and challenging model of KRAS G12V mutation. Additionally in an efficacy study with mice bearing SW1990 xenograft, at 10 mg/kg, qW, the compounds regressed the tumors by over 90%.
利益披露 Disclosure
C. Wang, None..
P. Ghosh, None..
S. Jin, None..
D. McEachern, None..
Q. Li, None..
B. Wen, None.
S. Wang,
Medsyn Biopharma g., Board of Directors, non-salaried role), Co-founder of Medsyn Biopharma, and own equity in Medsyn and a paid consultant of Medsyn.