Abstract

The overexpression of P21-activated kinase 1 (PAK1) is associated with poor prognosis in several cancers, which has emerged as a promising drug targets. Based on high-throughput virtual screening strategy, tetrahydrothieno [2,3-c]pyridine scaffold was identified as an initial lead for targeting PAK1. Herein we reported our structure-based optimisation strategy to discover a potent PAK1 inhibitor (7j) which displayed potent PAK1 inhibition and antiproliferatory activity in MDA-MB-231 cells. 7j induced obviously G2/M cell cycle arrest via PAK1-cdc25c-cdc2 pathway, and also inhibited MAPK-ERK and MAPK-JNK cascade to induce MDA-MB-231 cell death. Together, these results provided a novel chemical scaffold as PAK1 inhibitor for breast cancer treatment.

摘要

P21活化激酶1（PAK1）的过度表达与几种癌症的预后不良有关，这已成为一种有希望的药物靶标。基于高通量虚拟筛选策略，四氢噻吩并[2,3-c]吡啶骨架被确定为靶向PAK1的最初线索。在这里，我们报告了我们基于结构的优化策略，以发现有效的PAK1抑制剂（7j），该抑制剂在MDA-MB-231细胞中显示出有效的PAK1抑制和抗增殖活性。7j通过PAK1-cdc25c-cdc2途径明显诱导G2 / M细胞周期阻滞，并抑制MAPK-ERK和MAPK-JNK级联反应诱导MDA-MB-231细胞死亡。在一起，这些结果提供了一种新型化学支架作为PAK1抑制剂用于乳腺癌治疗。