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

Matsui Y, Yasumatsu I, Asahi T, Kitamura T, Kanai K, Ubukata O, Hayasaka H, Takaishi S, Hanzawa H, Katakura S
Bioorg Med Chem 25 3540-3546 (2017)
Cited: 12 times
EuropePMC logo PMID: 28511909

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.

Articles - 5x1v mentioned but not cited (1)

  1. Iridin Prevented Against Lipopolysaccharide-Induced Inflammatory Responses of Macrophages via Inactivation of PKM2-Mediated Glycolytic Pathways. Ying ZH, Li HM, Yu WY, Yu CH. J Inflamm Res 14 341-354 (2021)


Reviews citing this publication (4)

  1. The role of pyruvate kinase M2 in anticancer therapeutic treatments. Su Q, Luo S, Tan Q, Deng J, Zhou S, Peng M, Tao T, Yang X. Oncol Lett 18 5663-5672 (2019)
  2. Chemistry-driven Hit-to-lead Optimization Guided by Structure-based Approaches. Hoffer L, Muller C, Roche P, Morelli X. Mol Inform 37 e1800059 (2018)
  3. Pyruvate kinase activators as a therapy target: a patent review 2011-2017. Adem S, Comakli V, Uzun N. Expert Opin Ther Pat 28 61-68 (2018)
  4. Tumor pyruvate kinase M2 modulators: a comprehensive account of activators and inhibitors as anticancer agents. Rathod B, Chak S, Patel S, Shard A. RSC Med Chem 12 1121-1141 (2021)

Articles citing this publication (7)

  1. Discovery of novel naphthoquinone derivatives as inhibitors of the tumor cell specific M2 isoform of pyruvate kinase. Ning X, Qi H, Li R, Li Y, Jin Y, McNutt MA, Liu J, Yin Y. Eur J Med Chem 138 343-352 (2017)
  2. Structure-Guided Approach to Discover Tuberosin as a Potent Activator of Pyruvate Kinase M2, Targeting Cancer Therapy. Adnan M, Shamsi A, Elasbali AM, Siddiqui AJ, Patel M, Alshammari N, Alharethi SH, Alhassan HH, Bardakci F, Hassan MI. Int J Mol Sci 23 13172 (2022)
  3. PYK-SubstitutionOME: an integrated database containing allosteric coupling, ligand affinity and mutational, structural, pathological, bioinformatic and computational information about pyruvate kinase isozymes. Swint-Kruse L, Dougherty LL, Page B, Wu T, O'Neil PT, Prasannan CB, Timmons C, Tang Q, Parente DJ, Sreenivasan S, Holyoak T, Fenton AW. Database (Oxford) 2023 baad030 (2023)
  4. Purification and Characterization of Prolyl Hydroxylase 3/Pyruvate Kinase Isoform 2 Protein Complex. Kumar S, Patel AK. Mol Biotechnol 62 111-118 (2020)
  5. Chlorpromazine affects glioblastoma bioenergetics by interfering with pyruvate kinase M2. Abbruzzese C, Matteoni S, Matarrese P, Signore M, Ascione B, Iessi E, Gurtner A, Sacconi A, Ricci-Vitiani L, Pallini R, Pace A, Villani V, Polo A, Costantini S, Budillon A, Ciliberto G, Paggi MG. Cell Death Dis 14 821 (2023)
  6. Linking ATP and allosteric sites to achieve superadditive binding with bivalent EGFR kinase inhibitors. Wittlinger F, Ogboo BC, Shevchenko E, Damghani T, Pham CD, Schaeffner IK, Oligny BT, Chitnis SP, Beyett TS, Rasch A, Buckley B, Urul DA, Shaurova T, May EW, Schaefer EM, Eck MJ, Hershberger PA, Poso A, Laufer SA, Heppner DE. Commun Chem 7 38 (2024)
  7. Retracted Article: PKM2 overexpression protects against 6-hydroxydopamine-induced cell injury in the PC12 cell model of Parkinson's disease via regulation of the brahma-related gene 1/STAT3 pathway. Jiang L, Gao Y, Wang G, Zhong J. RSC Adv 9 14834-14840 (2019)


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