Molecular structures of cdc2-like kinases in complex with a new inhibitor chemotype

Cdc2-like kinases (CLKs) represent a family of serine-threonine kinases involved in the regulation of splicing by phosphorylation of SR-proteins and other splicing factors. Although compounds acting against CLKs have been described, only a few show selectivity against dual-specificity tyrosine phosphorylation regulated-kinases (DYRKs). We here report a novel CLK inhibitor family based on a 6,7-dihydropyrrolo[3,4-g]indol-8(1H)-one core scaffold. Within the series, 3-(3-chlorophenyl)-6,7-dihydropyrrolo[3,4-g]indol-8(1H)-one (KuWal151) was identified as inhibitor of CLK1, CLK2 and CLK4 with a high selectivity margin towards DYRK kinases. The compound displayed a potent antiproliferative activity in an array of cultured cancer cell lines. The X-ray structure analyses of three members of the new compound class co-crystallized with CLK proteins corroborated a molecular binding mode predicted by docking studies.

细胞周期蛋白依赖性激酶样激酶（Cdc2-like kinases, CLKs）是一类丝氨酸/苏氨酸激酶家族，可通过磷酸化SR蛋白（SR-proteins）及其他剪接因子调控RNA剪接过程。尽管已有针对CLKs的活性化合物被报道，但其中仅少数对双特异性酪氨酸磷酸化调节激酶（dual-specificity tyrosine phosphorylation regulated-kinases, DYRKs）具备较高选择性。本研究报道了一类基于6,7-二氢吡咯并[3,4-g]吲哚-8(1H)-酮母核骨架的新型CLK抑制剂。在该系列化合物中，3-(3-氯苯基)-6,7-二氢吡咯并[3,4-g]吲哚-8(1H)-酮（KuWal151）被鉴定为CLK1、CLK2及CLK4的抑制剂，且对DYRK激酶家族展现出优异的选择性。该化合物在一系列体外培养的癌细胞系中展现出强效的抗增殖活性。通过对3种该新型化合物与CLK蛋白共结晶产物的X射线晶体结构分析，验证了分子对接研究预测的结合模式。