Discovery of novel quinazoline-based covalent inhibitors of KRAS G12C with various cysteine-targeting warheads as potential anticancer agents

被引：19

作者：

Li, Ling ^{[1
]}

Zhao, Huiting ^{[1
]}

Liao, Hui ^{[1
]}

Chen, Jingxuan ^{[1
]}

Liu, Jin ^{[1
]}

Chen, Jianjun ^{[1
]}

机构：

[1] Southern Med Univ, Sch Pharmaceut Sci, Guangdong Prov Key Lab New Drug Screening, Guangzhou 510515, Peoples R China

来源：

BIOORGANIC CHEMISTRY | 2021年 / 110卷

关键词：

KRAS G12C; Covalent inhibitors; Anticancer; Cysteine-targeting warheads;

D O I：

10.1016/j.bioorg.2021.104825

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

A series of novel quinazoline analogs with a variety of cysteine-targeting warheads (electrophiles) were designed and synthesized based on ARS-1620 as covalent KRAS G12C inhibitors. Among them, compounds LLK10 and LLK14 exhibited similar or better antiproliferative activity than ARS-1620. LLK10 was used for subsequent biological studies due to the higher selectivity towards KRAS G12C-mutated cells than LLK14. LLK10 maintained the mechanism of action by forming a covalent bond with KRAS G12C protein, thus decreasing the level of phosphorylated Mek and Erk, and leading to tumor cell apoptosis. In addition, LLK10 was able to suppress the formation of H358 tumor colonies. Molecular modeling study indicated that LLK10 binds with high affinity to the SWII binding site in KRAS G12C and overlaps well with ARS-1620. The high binding affinity of LLK10 was further confirmed by the isothermal titration calorimetry (ITC) assay in which LLK10 exhibited a K-D of 115 nM for binding to KRAS G12C. These results suggest that the novel covalent inhibitors of KRAS G12C with different warheads deserve further investigation as potential anticancer agents.

引用

页数：9

共 11 条

[1] KRAS-mutant non-small cell lung cancer: Converging small molecules and immune checkpoint inhibition [J].