4JPG

2-((1H-benzo[d]imidazol-1-yl)methyl)-4H-pyrido[1,2-a]pyrimidin-4-ones as Novel PKM2 Activators

Summary for 4JPG

• Entry DOI: 10.2210/pdb4jpg/pdb
• Descriptor: Pyruvate kinase isozymes M1/M2, 1,6-di-O-phosphono-beta-D-fructofuranose, 2-(1H-benzimidazol-1-ylmethyl)-4H-pyrido[1,2-a]pyrimidin-4-one, ... (4 entities in total)
• Functional Keywords: pyruvate kinase, transferase-transferase activator complex, transferase/transferase activator
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 245725.36

Authors

Greasley, S.E.,Hickey, M.,Phonephaly, H.,Cronin, C. (deposition date: 2013-03-19, release date: 2013-05-22, Last modification date: 2024-02-28)

Primary citation

Guo, C.,Linton, A.,Jalaie, M.,Kephart, S.,Ornelas, M.,Pairish, M.,Greasley, S.,Richardson, P.,Maegley, K.,Hickey, M.,Li, J.,Wu, X.,Ji, X.,Xie, Z.
Discovery of 2-((1H-benzo[d]imidazol-1-yl)methyl)-4H-pyrido[1,2-a]pyrimidin-4-ones as novel PKM2 activators.
Bioorg.Med.Chem.Lett., 23:3358-3363, 2013

PubMed Abstract: The M2 isoform of pyruvate kinase is an emerging target for antitumor therapy. In this letter, we describe the discovery of 2-((1H-benzo[d]imidazol-1-yl)methyl)-4H-pyrido[1,2-a]pyrimidin-4-ones as potent and selective PKM2 activators which were found to have a novel binding mode. The original lead identified from high throughput screening was optimized into an efficient series via computer-aided structure-based drug design. Both a representative compound from this series and an activator described in the literature were used as molecular tools to probe the biological effects of PKM2 activation on cancer cells. Our results suggested that PKM2 activation alone is not sufficient to alter cancer cell metabolism.

PubMed: 23622982
DOI: 10.1016/j.bmcl.2013.03.090

Experimental method

X-RAY DIFFRACTION (2.33 Å)