Discovery of novel Quinazoline-based KRAS G12C inhibitors as potential anticancer agents

Bioorg Med Chem. 2022 Oct 1:71:116962. doi: 10.1016/j.bmc.2022.116962.

Ling Li ¹, Huiting Zhao ², Xiaopeng Peng ³, Jin Liu ², Ruiyao Mai ², Jingxuan Chen ², Lin Lin ⁴, Ting Chen ⁴, Jun Yan ⁵, Jiaolong Shi ⁶, Jianjun Chen ⁷

Affiliations

1 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.
2 School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou 510515, China.
3 College of Pharmacy, Gannan Medical University, Ganzhou 314000, China.
4 Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
5 Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China. Electronic address: yanjunfudan@163.com.
6 Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China. Electronic address: shijiaolong10@smu.edu.cn.
7 School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou 510515, China; Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China. Electronic address: jchen21@smu.edu.cn.

PMID: 35987104 DOI: 10.1016/j.bmc.2022.116962

Abstract

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 (IC₅₀ = 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_D = 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.

Keywords

5-nitrofuran-2-carboxylic acid; Anticancer; KRAS G12C.

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