In this section, you can access to the latest technical information related to the FUTURE project topic.

Synthesis of novel 7-azaindole derivatives containing pyridin-3-ylmethyl dithiocarbamate moietyas potent PKM2 activators and PKM2 nucleus translocation inhibitors

Multiple lines of evidence have indicated that pyruvate kinase M2 (PKM2) is upregulated in most cancer cells and it is increasingly recognized as a potential therapeutic target in oncology. In a continuation of our discovery of lead compound 5 and SAR study, the 7-azaindole moiety in compound 5 was systematically optimized. The results showed that compound 6f, which has a difluroethyl substitution on the 7-azaindole ring, exhibited high PKM2 activation potency and anti-proliferation activities on A375?cell lines. In a xenograft mouse model, oral administration of compound 6f led to significant tumor regression without obvious toxicity. Further mechanistic studies revealed that 6f could influence the translocation of PKM2 into nucleus, as well as induction of apoptosis and autophagy of A375?cells. More importantly, compound 6f significantly inhibited migration of A375?cells in a concentration-dependent manner. Collectively, 6f may serve as a lead compound in the development of potent PKM2 activators for cancer therapy.

» Author: Bin Liu, Xia Yuan, Bo Xu, Han Zhang, Ridong Li, Xin Wang, Zemei Ge, Runtao Li

» Reference: 10.1016/j.ejmech.2019.03.003

» Publication Date: 08/03/2019

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