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

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

Publication date: May 15, 2019

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 difluoroethyl 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.

Liu, B., Yuan, X., Xu, B., Zhang, H., Li, R., Wang, X., Ge, Z., and Li, R. Synthesis of novel 7-azaindole derivatives containing pyridin-3-ylmethyl dithiocarbamate moiety as potent PKM2 activators and PKM2 nucleus translocation inhibitors. 22603. 2019 Eur J Med Chem (170):

Concepts Keywords
Apoptosis Apoptosis
Autophagy Drug Screening
Lead Compound Thyroid hormones
Moiety Apoptosis
Nucleus MTOR
Oncology Pyruvate kinase
Pyruvate Kinase PKM2
Regression Functional groups
Ring Cell signaling
Toxicity Immunology
Translocation Programmed cell death
Tumor Signal transduction
Xenograft Branches of biology
Significant tumor

Semantics

Type Source Name
pathway BSID Melanoma
disease DOID Melanoma
disease MESH Melanoma
pathway BSID Apoptosis
disease MESH development
gene UNIPROT SMIM10L2A
gene UNIPROT SMIM10L2B
gene UNIPROT SARDH
gene UNIPROT NR1I2
gene UNIPROT SRL
disease DOID cancer
disease MESH cancer
disease MESH Multiple
gene UNIPROT PKM

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