BAY-069, a Novel (Trifluoromethyl)pyrimidinedione-Based BCAT1/2 Inhibitor and Chemical Probe

[Image: see text] The branched-chain amino acid transaminases (BCATs) are enzymes that catalyze the first reaction of catabolism of the essential branched-chain amino acids to branched-chain keto acids to form glutamate. They are known to play a key role in different cancer types. Here, we report a...

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Autores principales: Günther, Judith, Hillig, Roman C., Zimmermann, Katja, Kaulfuss, Stefan, Lemos, Clara, Nguyen, Duy, Rehwinkel, Hartmut, Habgood, Matthew, Lechner, Christian, Neuhaus, Roland, Ganzer, Ursula, Drewes, Mark, Chai, Jijie, Bouché, Léa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2022
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9661481/
https://www.ncbi.nlm.nih.gov/pubmed/36261130
http://dx.doi.org/10.1021/acs.jmedchem.2c00441
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author Günther, Judith
Hillig, Roman C.
Zimmermann, Katja
Kaulfuss, Stefan
Lemos, Clara
Nguyen, Duy
Rehwinkel, Hartmut
Habgood, Matthew
Lechner, Christian
Neuhaus, Roland
Ganzer, Ursula
Drewes, Mark
Chai, Jijie
Bouché, Léa
author_facet Günther, Judith
Hillig, Roman C.
Zimmermann, Katja
Kaulfuss, Stefan
Lemos, Clara
Nguyen, Duy
Rehwinkel, Hartmut
Habgood, Matthew
Lechner, Christian
Neuhaus, Roland
Ganzer, Ursula
Drewes, Mark
Chai, Jijie
Bouché, Léa
author_sort Günther, Judith
collection PubMed
description [Image: see text] The branched-chain amino acid transaminases (BCATs) are enzymes that catalyze the first reaction of catabolism of the essential branched-chain amino acids to branched-chain keto acids to form glutamate. They are known to play a key role in different cancer types. Here, we report a new structural class of BCAT1/2 inhibitors, (trifluoromethyl)pyrimidinediones, identified by a high-throughput screening campaign and subsequent optimization guided by a series of X-ray crystal structures. Our potent dual BCAT1/2 inhibitor BAY-069 displays high cellular activity and very good selectivity. Along with a negative control (BAY-771), BAY-069 was donated as a chemical probe to the Structural Genomics Consortium.
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spelling pubmed-96614812022-11-15 BAY-069, a Novel (Trifluoromethyl)pyrimidinedione-Based BCAT1/2 Inhibitor and Chemical Probe Günther, Judith Hillig, Roman C. Zimmermann, Katja Kaulfuss, Stefan Lemos, Clara Nguyen, Duy Rehwinkel, Hartmut Habgood, Matthew Lechner, Christian Neuhaus, Roland Ganzer, Ursula Drewes, Mark Chai, Jijie Bouché, Léa J Med Chem [Image: see text] The branched-chain amino acid transaminases (BCATs) are enzymes that catalyze the first reaction of catabolism of the essential branched-chain amino acids to branched-chain keto acids to form glutamate. They are known to play a key role in different cancer types. Here, we report a new structural class of BCAT1/2 inhibitors, (trifluoromethyl)pyrimidinediones, identified by a high-throughput screening campaign and subsequent optimization guided by a series of X-ray crystal structures. Our potent dual BCAT1/2 inhibitor BAY-069 displays high cellular activity and very good selectivity. Along with a negative control (BAY-771), BAY-069 was donated as a chemical probe to the Structural Genomics Consortium. American Chemical Society 2022-10-19 2022-11-10 /pmc/articles/PMC9661481/ /pubmed/36261130 http://dx.doi.org/10.1021/acs.jmedchem.2c00441 Text en © 2022 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by-nc-nd/4.0/Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Günther, Judith
Hillig, Roman C.
Zimmermann, Katja
Kaulfuss, Stefan
Lemos, Clara
Nguyen, Duy
Rehwinkel, Hartmut
Habgood, Matthew
Lechner, Christian
Neuhaus, Roland
Ganzer, Ursula
Drewes, Mark
Chai, Jijie
Bouché, Léa
BAY-069, a Novel (Trifluoromethyl)pyrimidinedione-Based BCAT1/2 Inhibitor and Chemical Probe
title BAY-069, a Novel (Trifluoromethyl)pyrimidinedione-Based BCAT1/2 Inhibitor and Chemical Probe
title_full BAY-069, a Novel (Trifluoromethyl)pyrimidinedione-Based BCAT1/2 Inhibitor and Chemical Probe
title_fullStr BAY-069, a Novel (Trifluoromethyl)pyrimidinedione-Based BCAT1/2 Inhibitor and Chemical Probe
title_full_unstemmed BAY-069, a Novel (Trifluoromethyl)pyrimidinedione-Based BCAT1/2 Inhibitor and Chemical Probe
title_short BAY-069, a Novel (Trifluoromethyl)pyrimidinedione-Based BCAT1/2 Inhibitor and Chemical Probe
title_sort bay-069, a novel (trifluoromethyl)pyrimidinedione-based bcat1/2 inhibitor and chemical probe
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9661481/
https://www.ncbi.nlm.nih.gov/pubmed/36261130
http://dx.doi.org/10.1021/acs.jmedchem.2c00441
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