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The Discovery of in Vivo Active Mitochondrial Branched-Chain Aminotransferase (BCATm) Inhibitors by Hybridizing Fragment and HTS Hits.

Bertrand SM, Ancellin N, Beaufils B, Bingham RP, Borthwick JA, Boullay AB, Boursier E, Carter PS, Chung CW, Churcher I, Dodic N, Fouchet MH, Fournier C, Francis PL, Gummer LA, Herry K, Hobbs A, Hobbs CI, Homes P, Jamieson C, Nicodeme E, Pickett SD, Reid IH, Simpson GL, Sloan LA, Smith SE, Somers DO, Spitzfaden C, Suckling CJ, Valko K, Washio Y, Young RJ
J Med Chem 58 7140-63 (2015)
Related entries: 5bwr, 5bwt, 5bwu, 5bww, 5bwx

Cited: 14 times
EuropePMC logo PMID: 26090771

Abstract

The hybridization of hits, identified by complementary fragment and high throughput screens, enabled the discovery of the first series of potent inhibitors of mitochondrial branched-chain aminotransferase (BCATm) based on a 2-benzylamino-pyrazolo[1,5-a]pyrimidinone-3-carbonitrile template. Structure-guided growth enabled rapid optimization of potency with maintenance of ligand efficiency, while the focus on physicochemical properties delivered compounds with excellent pharmacokinetic exposure that enabled a proof of concept experiment in mice. Oral administration of 2-((4-chloro-2,6-difluorobenzyl)amino)-7-oxo-5-propyl-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carbonitrile 61 significantly raised the circulating levels of the branched-chain amino acids leucine, isoleucine, and valine in this acute study.

Reviews citing this publication (5)

  1. The ways and means of fragment-based drug design. Doak BC, Norton RS, Scanlon MJ. Pharmacol. Ther. 167 28-37 (2016)
  2. Current perspectives in fragment-based lead discovery (FBLD). Lamoree B, Hubbard RE. Essays Biochem. 61 453-464 (2017)
  3. Key Enzymes Involved in the Synthesis of Hops Phytochemical Compounds: From Structure, Functions to Applications. Hong K, Wang L, Johnpaul A, Lv C, Ma C. Int J Mol Sci 22 9373 (2021)
  4. The mechanism of branched-chain amino acid transferases in different diseases: Research progress and future prospects. Nong X, Zhang C, Wang J, Ding P, Ji G, Wu T. Front Oncol 12 988290 (2022)
  5. Insights into the medicinal chemistry of heterocycles integrated with a pyrazolo[1,5-a]pyrimidine scaffold. Hammouda MM, Gaffer HE, Elattar KM. RSC Med Chem 13 1150-1196 (2022)

Articles citing this publication (9)

  1. Discovery and Optimization of Potent, Selective, and in Vivo Efficacious 2-Aryl Benzimidazole BCATm Inhibitors. Deng H, Zhou J, Sundersingh F, Messer JA, Somers DO, Ajakane M, Arico-Muendel CC, Beljean A, Belyanskaya SL, Bingham R, Blazensky E, Boullay AB, Boursier E, Chai J, Carter P, Chung CW, Daugan A, Ding Y, Herry K, Hobbs C, Humphries E, Kollmann C, Nguyen VL, Nicodeme E, Smith SE, Dodic N, Ancellin N. ACS Med Chem Lett 7 379-384 (2016)
  2. Fragment Screening of Soluble Epoxide Hydrolase for Lead Generation-Structure-Based Hit Evaluation and Chemistry Exploration. Xue Y, Olsson T, Johansson CA, Öster L, Beisel HG, Rohman M, Karis D, Bäckström S. ChemMedChem 11 497-508 (2016)
  3. Trends in Hit-to-Lead Optimization Following DNA-Encoded Library Screens. Reiher CA, Schuman DP, Simmons N, Wolkenberg SE. ACS Med Chem Lett 12 343-350 (2021)
  4. Intact Protein Analysis at 21 Tesla and X-Ray Crystallography Define Structural Differences in Single Amino Acid Variants of Human Mitochondrial Branched-Chain Amino Acid Aminotransferase 2 (BCAT2). Anderson LC, Håkansson M, Walse B, Nilsson CL. J. Am. Soc. Mass Spectrom. 28 1796-1804 (2017)
  5. BAY-069, a Novel (Trifluoromethyl)pyrimidinedione-Based BCAT1/2 Inhibitor and Chemical Probe. Günther J, Hillig RC, Zimmermann K, Kaulfuss S, Lemos C, Nguyen D, Rehwinkel H, Habgood M, Lechner C, Neuhaus R, Ganzer U, Drewes M, Chai J, Bouché L. J Med Chem 65 14366-14390 (2022)
  6. BCATc inhibitor 2 ameliorated mitochondrial dysfunction and apoptosis in oleic acid-induced non-alcoholic fatty liver disease model. Lu Z, Sun GF, Pan XA, Qu XH, Yang P, Chen ZP, Han XJ, Wang T. Front Pharmacol 13 1025551 (2022)
  7. Branched-Chain Amino Acid Metabolism in the Failing Heart. Karwi QG, Lopaschuk GD. Cardiovasc Drugs Ther (2022)
  8. Combining structural and coevolution information to unveil allosteric sites. La Sala G, Pfleger C, Käck H, Wissler L, Nevin P, Böhm K, Janet JP, Schimpl M, Stubbs CJ, De Vivo M, Tyrchan C, Hogner A, Gohlke H, Frolov AI. Chem Sci 14 7057-7067 (2023)
  9. Integration of Lead Discovery Tactics and the Evolution of the Lead Discovery Toolbox. Leveridge M, Chung CW, Gross JW, Phelps CB, Green D. SLAS Discov 23 881-897 (2018)


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