Development of Novel Irreversible Pyruvate Kinase M2 Inhibitors
Journal
Journal of Medicinal Chemistry
Journal Volume
62
Journal Issue
18
Pages
8497-8510
Date Issued
2019
Author(s)
Hsieh, I.-S.
Gopula, B.
Chou, C.-C.
Wu, H.-Y.
Chang, G.-D.
Wu, W.-J.
Chang, C.-S.
Chu, P.-C.
Chen, C.S.
Abstract
As cancer cells undergo metabolic reprogramming in the course of tumorigenesis, targeting energy metabolism represents a promising strategy in cancer therapy. Among various metabolic enzymes examined, pyruvate kinase M2 type (PKM2) has received much attention in light of its multifaceted function in promoting tumor growth and progression. In this study, we reported the development of a novel irreversible inhibitor of PKM2, compound 1, that exhibits a differential tumor-suppressive effect among an array of cancer cell lines. We further used a clickable activity-based protein profiling (ABPP) probe and SILAC coupled with LC-MS/MS to identify the Cys-317 and Cys-326 residues of PKM2 as the covalent binding sites. Equally important, compound 1 at 10 mg/kg was effective in suppressing xenograft tumor growth in nude mice without causing acute toxicity by targeting both metabolic and oncogenic functions. Together, these data suggest its translational potential to foster new strategies for cancer therapy. ? 2019 American Chemical Society.
SDGs
Other Subjects
1 (4' methoxy [1,1' biphenyl] 4 yl)ethan 1 one; 3 (1 (4 aminophenyl) 5 (4' (prop 2 yn 1 yloxy) [1,1' -biphenyl] 4 yl) 1h pyrazol 3 yl) n methylpropanamide; 3 (5 (4' hydroxy [1,1' biphenyl] 4 yl) 1 (4 nitrophenyl) 1h pyrazol 3 yl) n methyl propanamide; 3 (5 (4' methoxy [1,1' biphenyl] 4 yl) 1 (4 nitrophenyl) 1h pyrazol 3 yl) n methyl propanamide; cysteine; ethyl 3 (5 (4' methoxy [1,1' biphenyl] 4 yl) 1 (4 nitrophenyl) 1h pyrazol 3 yl) propanoate; ethyl 4 (1h benzo[d][1,2,3]triazol 1 yl) 4 oxobutanoate; ethyl 4 hydroxy 6 (4' methoxy [1,1' biphenyl] 4 yl) 6 oxo hex 4 enoate; n (4 (3 (3 (methylamino) 3 oxopropyl) 5 (4' (prop 2 yn 1 yloxy) [1,1' biphenyl] 4 yl) 1h pyrazol 1 yl)phenyl)propiolamide; n (4 (3 (3 (methylamino) 3 oxopropyl) 5 (4' (trifluoromethyl) [1,1' biphenyl] 4 yl) 1h pyrazol 1 yl)phenyl)propiolamide; n methyl 3 (1 (4 nitrophenyl) 5 (4' (prop 2 yn 1 yloxy) [1,1' biphenyl] 4 yl) 1h pyrazol 3 yl)propanamide; phosphotransferase inhibitor; pyruvate kinase; pyruvate kinase M2; unclassified drug; carrier protein; enzyme inhibitor; membrane protein; peptide; reactive oxygen metabolite; thyroid hormone; thyroid hormone-binding proteins; animal experiment; animal model; antineoplastic activity; Article; AsPC-1 cell line; cancer cell line; cancer inhibition; cancer therapy; carbon nuclear magnetic resonance; carcinogenesis; chemical structure; drug synthesis; glycolysis; human; human cell; IC50; in vivo study; liquid chromatography-mass spectrometry; LNCaP cell line; MCF-7 cell line; MDA-MB-231 cell line; MIA PaCa-2 cell line; mouse; MTT assay; NCI-H157 cell line; NCI-H1650 cell line; NCI-H1975 cell line; NCI-H460 cell line; nonhuman; PANC-1 cell line; PC-3 [Human lung carcinoma] cell line; PC-9 cell line; proton nuclear magnetic resonance; SCC-4 cell line; SCC2095 cell line; tumor xenograft; animal; cancer transplantation; cell proliferation; chemistry; drug design; female; liquid chromatography; neoplasm; nude mouse; proteomics; tandem mass spectrometry; tumor cell line; Animals; Carcinogenesis; Carrier Proteins; Cell Line, Tumor; Cell Proliferation; Chromatography, Liquid; Cysteine; Drug Design; Enzyme Inhibitors; Female; Glycolysis; Humans; MCF-7 Cells; Membrane Proteins; Mice; Mice, Nude; Neoplasm Transplantation; Neoplasms; PC-3 Cells; Peptides; Proteomics; Reactive Oxygen Species; Tandem Mass Spectrometry; Thyroid Hormones
Type
journal article