Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, PR China.
Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, 211198, PR China.
Eur J Med Chem. 2024 Dec 15;280:116952. doi: 10.1016/j.ejmech.2024.116952. Epub 2024 Oct 9.
Targeted inhibition of the Wnt pathway is a promising strategy for treating NSCLC. CDC2-like kinase 2 (CLK2), a dual-specificity kinase responsible for phosphorylating serine/arginine-rich (SR) proteins, can modulate Wnt signaling through the alternative splicing of Wnt target genes, making CLK2 an attractive therapeutic target for NSCLC. In this study, we report the synthesis, optimization, and evaluation of CLK2 inhibitors that effectively suppress the proliferation of NSCLC cells, with the identification of the lead compound LBM22. Notably, compound LBM22 demonstrated potent inhibition of CLK2 (IC = 3.9 nM), leading to broad suppression of NSCLC cells proliferation and induction of apoptosis. Furthermore, LBM22 dose-dependently suppressed SR protein phosphorylation (pSRSF4, pSRSF5, and pSRSF6) in NSCLC cells, while downregulating the expression of Wnt pathway-related proteins (p-β-catenin, Axin 2, and c-Myc) as well as anti-apoptotic proteins (Bcl-2 and Mcl-1). Additionally, significant antiproliferative activity was observed for LBM22 in 3D cultured H1975OR cells. In conclusion, LBM22 emerges as a promising CLK2 inhibitor for the treatment of NSCLC.
靶向抑制 Wnt 通路是治疗 NSCLC 的一种有前途的策略。CDC2 样激酶 2（CLK2）是一种双特异性激酶，负责磷酸化丝氨酸/精氨酸丰富（SR）蛋白，通过 Wnt 靶基因的选择性剪接可以调节 Wnt 信号，使 CLK2 成为 NSCLC 的一个有吸引力的治疗靶点。在这项研究中，我们报告了 CLK2 抑制剂的合成、优化和评估，这些抑制剂能有效抑制 NSCLC 细胞的增殖，确定了先导化合物 LBM22。值得注意的是，化合物 LBM22 对 CLK2 具有很强的抑制作用（IC = 3.9 nM），导致广泛抑制 NSCLC 细胞的增殖并诱导细胞凋亡。此外，LBM22 剂量依赖性地抑制 NSCLC 细胞中 SR 蛋白磷酸化（pSRSF4、pSRSF5 和 pSRSF6），同时下调 Wnt 通路相关蛋白（p-β-catenin、Axin 2 和 c-Myc）和抗凋亡蛋白（Bcl-2 和 Mcl-1）的表达。此外，LBM22 在 3D 培养的 H1975OR 细胞中表现出显著的抗增殖活性。总之，LBM22 是一种很有前途的治疗 NSCLC 的 CLK2 抑制剂。
