期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 233, 期 -, 页码 -出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2022.114243
关键词
KRAS G12D inhibitor; Anticancer; Combinatorial chemistry
资金
- Southern Medical University of China [C1051008]
- Organization Department of the CPC Central Committee, China [C1080092]
- International Science and Technology Cooperation Projects of Guangdong Province [2018A050506037]
A series of novel thieno[2,3-d]pyrimidine analogs were designed and synthesized as KRAS G12D inhibitors. Compound KD-8 exhibited potent antiproliferative activity and antitumor efficacy by decreasing the active form of KRAS and inhibiting Raf and Erk in KRAS G12D mutated cancer cell lines.
A series of novel thieno[2,3-d]pyrimidine analogs were designed and synthesized as KRAS G12D inhibitors via combinatorial virtual screening approach. Most compounds exhibited potent antiproliferative activity on KRAS G12D mutated cancer cell lines (Panc1, SW1990 and CT26) with IC50 values in the low micromolar range. Among them, compound KD-8 showed the highest antiproliferative activity with an average IC50 of 2.1 mM against three KRAS G12D-mutated cells (Panc1, SW1990 and CT26). KD-8 decreased the active form of KRAS (KRAS-GTP) in KRAS G12D mutated cancer cell lines (CT26 and SW1990) but not in KRAS G13D mutated cancer cells (HCT116). Moreover, KD-8 down-regulated the phosphorylated Raf and Erk in CT26 and SW1990 cancer cell lines but not in HeLa cells (KRAS WT). The binding affinity of KD-8 was further confirmed by the isothermal titration calorimetry (ITC) assay in which KD-8 exhibited a KD of 33 nM for binding to KRAS G12D protein. In addition, KD-8 (40 mg/kg or 60 mg/kg) exhibited significant antitumor efficacy in a CT26 tumor model with a tumor growth inhibition (TGI) of 42% or 53% without causing apparent toxicity. Taken together the above results suggest that KD-8 is a promising KRAS G12D inhibitor deserving further investigation. (c) 2022 Elsevier Masson SAS. All rights reserved.
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