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Design, synthesis and biological evaluation of novel tetrahydrothieno [2,3-c]pyridine substitued benzoyl thiourea derivatives as PAK1 inhibitors in triple negative breast cancer

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...

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Detalles Bibliográficos
Autores principales: Yao, Dahong, Huang, Jian, Wang, Jinhui, He, Zhendan, Zhang, Jin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470115/
https://www.ncbi.nlm.nih.gov/pubmed/32752894
http://dx.doi.org/10.1080/14756366.2020.1797710
Descripción
Sumario: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.