Discovery and structure-guided fragment-linking of 4-(2,3-dichlorobenzoyl)-1-methyl-pyrrole-2-carboxamide as a pyruvate kinase M2 activator

Bioorganic & Medicinal Chemistry
Yumi MatsuiShinichi Katakura

Abstract

Tumor cells switch glucose metabolism to aerobic glycolysis by expressing the pyruvate kinase M2 isoform (PKM2) in a low active form, providing glycolytic intermediates as building blocks for biosynthetic processes, and thereby supporting cell proliferation. Activation of PKM2 should invert aerobic glycolysis to an oxidative metabolism and prevent cancer growth. Thus, PKM2 has gained attention as a promising cancer therapy target. To obtain novel PKM2 activators, we conducted a high-throughput screening (HTS). Among several hit compounds, a fragment-like hit compound with low potency but high ligand efficiency was identified. Two molecules of the hit compound bound at one activator binding site, and the molecules were linked based on the crystal structure. Since this linkage succeeded in maintaining the original position of the hit compound, the obtained compound exhibited highly improved potency in an in vitro assay. The linked compound also showed PKM2 activating activity in a cell based assay, and cellular growth inhibition of the A549 cancer cell line. Discovery of this novel scaffold and binding mode of the linked compound provides a valuable platform for the structure-guided design of PKM2 activators.

Citations

Oct 11, 2017·Expert Opinion on Therapeutic Patents·Sevki AdemNaim Uzun
Jul 28, 2018·Molecular Informatics·Laurent HofferXavier Morelli
Dec 4, 2019·Oncology Letters·Qiongli SuXiaoping Yang
Nov 25, 2019·Molecular Biotechnology·Sunil Kumar, Ashok Kumar Patel
Jun 17, 2020·Journal of Medicinal Chemistry·Alexandre BancetIsabelle Krimm
Nov 22, 2018·Journal of Medicinal Chemistry·Paul N MortensonChristopher N Johnson
Nov 3, 2021·Journal of Medicinal Chemistry·Sahil AroraRaj Kumar

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