School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou 510515, China.
School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou 510515, China.
Bioorg Chem. 2021 Dec;117:105447. doi: 10.1016/j.bioorg.2021.105447. Epub 2021 Oct 22.
A series of KRAS G12C-targeting PROTACs (PROteolysis TArgeting Chimeras) were designed and synthesized based on KRas G12C-IN-3 (a KRAS G12C inhibitor) and pomalidomide as degraders of KRAS G12C with a molecular weight of < 900. Among them, compound KP-14 (m.w. = 852.16; tPSA = 174.53) showed the highest KRAS G12C-degrading capability in NCI-H358 cancer cells (DC≈1.25 μM). KP-14 bound to KRAS G12C through the acrylamide warhead and recruited the E3 ligase CRBN, causing rapid and sustained KRAS G12C degradation which led to suppression of MAPK signaling pathway in NCI-H358 cells. In addition, KP-14 selectively induced the degradation of KRAS G12C but not other KRAS isoforms such as G13D via PROTAC mechanism. Furthermore, KP-14 exhibited potent antiproliferative activity against NCI-H358 cancer cells and was able to suppress the formation of NCI-H358 tumor colonies. Collectively, this work suggests that KP-14 may serve as a tool compound for exploring the degradation of KRAS G12C by PROTAC strategy and deserve further investigation as a potential anticancer agent.
基于 KRas G12C-IN-3（一种 KRAS G12C 抑制剂）和泊马度胺（一种 KRAS G12C 的降解剂），我们设计并合成了一系列 KRAS G12C 靶向 PROTACs（蛋白水解靶向嵌合体）。这些 PROTACs 的分子量均小于 900。其中，化合物 KP-14（分子量=852.16；tPSA=174.53）在 NCI-H358 癌细胞中显示出最强的 KRAS G12C 降解能力（DC≈1.25μM）。KP-14 通过丙烯酰胺弹头与 KRAS G12C 结合，并募集 E3 连接酶 CRBN，导致 KRAS G12C 的快速和持续降解，从而抑制了 NCI-H358 细胞中的 MAPK 信号通路。此外，KP-14 通过 PROTAC 机制选择性诱导 KRAS G12C 的降解，而不诱导其他 KRAS 同工型（如 G13D）的降解。此外，KP-14 对 NCI-H358 癌细胞表现出强大的增殖抑制活性，并能够抑制 NCI-H358 肿瘤集落的形成。总之，这项工作表明，KP-14 可能作为一种工具化合物，用于探索通过 PROTAC 策略降解 KRAS G12C，并值得进一步研究作为一种潜在的抗癌剂。
