Akt (protein kinase B) is a master regulator of cell survival in response to growth factors. In human cancers, Akt plays a pivotal role in cell growth, apoptosis inhibition, protein synthesis, and glucose and fatty acid metabolism by phosphorylating its substrates, including CDK2, FOXO, GSK-3beta, S6 kinase, and mTOR[2]. Afuresertib, a thiophenecarboxamide derivative, is a catalytic ATP‐competitive inhibitor of AKT1, AKT2, AKT3 with Ki values of 0.08 nM, 2 nM, and 2.6 nM[3]. Afuresertib, an ATP‐competitive specific Akt inhibitor, exerted tumor‐specific effects on MPM cells. Afuresertib significantly increased caspase‐3 and caspase‐7 activities and apoptotic cell number among ACC-MESO-4 and MSTO-211H cells. Moreover, Afuresertib strongly arrested the cell cycle in the G1 phase[2]. Cells treated with Afuresertib show decreased phosphorylation of several substrates downstream of AKT. Afuresertib at 5 μmol/L for 24h clearly suppressed the migration of ACC-MESO-4 and MSTO-211H cells[3]. In a phase IIa study of Afuresertib, patients were treated with oral Afuresertib (125 mg/d) for over 28 weeks, it was showed that Afuresertib had clinical activity in some patients with newly diagnosed and advanced LCH[4].
搜索
