Cylene Pharmaceuticals, 5820 Nancy Ridge Drive, Suite 200, San Diego, CA 92121, USA.
Bioorg Med Chem Lett. 2011 Nov 15;21(22):6687-92. doi: 10.1016/j.bmcl.2011.09.059. Epub 2011 Sep 22.
A novel class of pan-Pim kinase inhibitors was designed by modifying the CK2 inhibitor CX-4945. Introduction of a triazole or secondary amide functionality on the C-7 position and 2'-halogenoanilines on C-5 resulted in potent inhibitors of the Pim-1 and Pim-2 isoforms, with many analogs active at single digit nanomolar concentrations. The molecules inhibited the phosphorylation at Serine 112 of the apoptosis effector BAD, and had potent antiproliferative effects on the AML cell line MV-4-11 (IC(50) <30 nM). This work delivers an excellent lead-optimization platform for Pim targeting anticancer therapies.
设计了一类新型的泛 Pim 激酶抑制剂，方法是对 CK2 抑制剂 CX-4945 进行修饰。在 C-7 位引入三唑或仲酰胺官能团，在 C-5 位引入 2'-卤代苯胺，得到了对 Pim-1 和 Pim-2 同工型具有很强抑制作用的抑制剂，许多类似物在纳摩尔浓度的个位数时就具有活性。这些分子抑制了凋亡效应物 BAD 的丝氨酸 112 的磷酸化，对 AML 细胞系 MV-4-11（IC(50) <30 nM）具有很强的抗增殖作用。这项工作为 Pim 靶向抗癌疗法提供了一个极好的先导优化平台。
