1001020-08-1Relevant articles and documents
Design, synthesis and biological evaluation of novel tetrahydrothieno [2,3-c]pyridine substitued benzoyl thiourea derivatives as PAK1 inhibitors in triple negative breast cancer
Yao, Dahong,Huang, Jian,Wang, Jinhui,He, Zhendan,Zhang, Jin
, p. 1524 - 1538 (2020)
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.
HEARING LOSS-PROTECTIVE COMPOUNDS AND METHODS THEREOF
-
Page/Page column 33; 34, (2020/03/02)
Disclosed herein are compounds, and pharmaceutical compositions that include such compounds, for preventing, treating, and/or protecting against sensory hair cell death. Methods of using the compounds, alone or in combination with other therapeutic agents, are also disclosed.
Discovery of a Novel Dual-Target Inhibitor of ERK1 and ERK5 That Induces Regulated Cell Death to Overcome Compensatory Mechanism in Specific Tumor Types
Wang, Guan,Zhao, Yuqian,Liu, Yao,Sun, Dejuan,Zhen, Yongqi,Liu, Jie,Fu, Leilei,Zhang, Lan,Ouyang, Liang
, p. 3976 - 3995 (2020/05/27)
ERK1 and ERK5 are proposed to have pivotal roles in several types of cancer. Under some circumstance, ERK5 may provide a common bypass route, which rescues proliferation upon abrogation of ERK1 signaling. Thus, we accurately classified the tumor types from The Cancer Genome Atlas (TCGA) based on the expression levels of ERK1 and ERK5. We proposed a novel therapeutic strategy to overcome the above-mentioned compensatory mechanism in specific tumor types by co-targeting both ERK1 and ERK5. On the basis of the idea of overcoming ERK5 compensation mechanism, 22ac (ADTL-EI1712) as the first selective dual-target inhibitor of ERK1 and ERK5 was discovered to have potent antitumor effects in vitro and in vivo. Interestingly, this compound was found to induce regulated cell death accompanied by autophagy in MKN-74 cells. Taken together, our results warrant the potential of this dual-target inhibitor as a new candidate drug that conquers compensatory mechanism in certain tumor types.
