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 May;110:104825. doi: 10.1016/j.bioorg.2021.104825. Epub 2021 Mar 13.
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 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.
基于 ARS-1620 作为共价 KRAS G12C 抑制剂，我们设计并合成了一系列具有各种半胱氨酸靶向弹头（亲电试剂）的新型喹唑啉类似物。其中，化合物 LLK10 和 LLK14 表现出与 ARS-1620 相似或更好的抗增殖活性。由于 LLK10 对 KRAS G12C 突变细胞的选择性高于 LLK14，因此它被用于后续的生物学研究。LLK10 通过与 KRAS G12C 蛋白形成共价键，从而降低磷酸化 Mek 和 Erk 的水平，导致肿瘤细胞凋亡，维持其作用机制。此外，LLK10 能够抑制 H358 肿瘤集落的形成。分子建模研究表明，LLK10 以高亲和力结合 KRAS G12C 的 SWII 结合位点，与 ARS-1620 重叠良好。等温滴定量热法（ITC）实验进一步证实了 LLK10 的高结合亲和力，其对 KRAS G12C 的 Kd 值为 115 nM。这些结果表明，具有不同弹头的新型 KRAS G12C 共价抑制剂作为潜在的抗癌药物值得进一步研究。
