Li Ling, Zhao Huiting, Peng Xiaopeng, Liu Jin, Mai Ruiyao, Chen Jingxuan, Lin Lin, Chen Ting, Yan Jun, Shi Jiaolong, Chen Jianjun
The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen 518033, China; 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 Med Chem. 2022 Oct 1;71:116962. doi: 10.1016/j.bmc.2022.116962. Epub 2022 Aug 5.
A series of novel quinazoline analogs were designed and synthesized based on ARS-1620 and LLK-10 (a KRAS inhibitor reported by us recently) as KRAS G12C inhibitors with a 5-nitrofuran-2-carboxylic acid warhead. Most of the newly synthesized compounds exhibited antiproliferative activities similar to or better than ARS-1620 and LLK-10. Among them, compound KS-19 showed the highest activity (IC = 460 ∼ 870 nM) and reasonable selectivity (3 to 27-fold) for inhibiting the proliferation of KRAS G12C-mutated cells (NCI-H358 and NCI-H23) over other KRAS mutant (e.g. G13D, G12D, G12S, G12V, WT) cancer cells. ITC, KRAS-GTP pull-down assay and western blot analysis demonstrated that KS-19 could bind to KRAS G12C protein with high affinity (K = 97 nM), thus decreasing the active form of KRAS G12C (KRAS G12C-GTP) and phosphorylated Erk, and leading to NCI-H358 tumor cell apoptosis. In addition, KS-19 was able to suppress the formation of NCI-H358 and NCI-H23 tumor colonies in a dose-dependent manner. Moreover, in vivo efficacy studies indicated that KS-19 (40 mg/kg) was effective in suppressing tumor growth in nude mice bearing NCI-H358 tumor xenografts with a TGI (tumor growth inhibition) of 47 %, comparable to that of ARS-1620 (50 %). Lastly, KS-19 possessed a benign toxicity profile without causing bone marrow suppression and any obvious morphological abnormalities in major organs of mice. Collectively, these results suggest that KS-19 represents a novel inhibitor of KRAS G12C worthy of further investigation as a potential anticancer agent.
基于ARS-1620和LLK-10（我们最近报道的一种KRAS抑制剂）设计并合成了一系列新型喹唑啉类似物，作为带有5-硝基呋喃-2-羧酸弹头的KRAS G12C抑制剂。大多数新合成的化合物表现出与ARS-1620和LLK-10相似或更好的抗增殖活性。其中，化合物KS-19表现出最高活性（IC = 460 ∼ 870 nM），并且在抑制KRAS G12C突变细胞（NCI-H358和NCI-H23）增殖方面对其他KRAS突变（如G13D、G12D、G12S、G12V、WT）癌细胞具有合理的选择性（3至27倍）。等温滴定量热法、KRAS-GTP下拉试验和蛋白质印迹分析表明，KS-19可以与KRAS G12C蛋白高亲和力结合（K = 97 nM），从而降低KRAS G12C的活性形式（KRAS G12C-GTP）和磷酸化的Erk，并导致NCI-H358肿瘤细胞凋亡。此外，KS-19能够以剂量依赖性方式抑制NCI-H358和NCI-H23肿瘤集落的形成。此外，体内药效学研究表明，KS-19（40 mg/kg）可有效抑制携带NCI-H358肿瘤异种移植瘤的裸鼠肿瘤生长，肿瘤生长抑制率（TGI）为47%，与ARS-1620（50%）相当。最后，KS-19具有良好的毒性特征，不会导致骨髓抑制，也不会在小鼠主要器官中引起任何明显的形态异常。总的来说，这些结果表明KS-19是一种新型的KRAS G12C抑制剂，作为一种潜在的抗癌药物值得进一步研究。
