From PROTAC to inhibitor: Structure-guided discovery of potent and orally bioavailable BET inhibitors.

Autor: Koravovic M; University of Belgrade, Faculty of Pharmacy, Department of Organic Chemistry, Vojvode Stepe 450, 11221, Belgrade, Serbia., Mayasundari A; Department of Chemical Biology & Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA., Tasic G; University of Belgrade, Faculty of Pharmacy, Department of Organic Chemistry, Vojvode Stepe 450, 11221, Belgrade, Serbia., Keramatnia F; Department of Chemical Biology & Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA., Stachowski TR; Department of Chemical Biology & Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA., Cui H; Department of Chemistry, University of Minnesota, 207 Pleasant Street SE, Minneapolis, MN, 55455, United States., Chai SC; Department of Chemical Biology & Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA., Jonchere B; Department of Tumour Cell Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA., Yang L; Department of Chemical Biology & Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA., Li Y; Department of Chemical Biology & Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA., Fu X; Department of Chemical Biology & Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA., Hiltenbrand R; Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA., Paul L; Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA., Mishra V; Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA., Klco JM; Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA., Roussel MF; Department of Tumour Cell Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA., Pomerantz WC; Department of Chemistry, University of Minnesota, 207 Pleasant Street SE, Minneapolis, MN, 55455, United States., Fischer M; Department of Chemical Biology & Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA., Rankovic Z; Department of Chemical Biology & Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA. Electronic address: zoran.rankovic@stjude.org., Savic V; University of Belgrade, Faculty of Pharmacy, Department of Organic Chemistry, Vojvode Stepe 450, 11221, Belgrade, Serbia. Electronic address: vladimir.savic@pharmacy.bg.ac.rs.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2023 May 05; Vol. 251, pp. 115246. Date of Electronic Publication: 2023 Mar 04.
DOI: 10.1016/j.ejmech.2023.115246
Abstrakt: An X-ray structure of a CLICK chemistry-based BET PROTAC bound to BRD2(BD2) inspired synthesis of JQ1 derived heterocyclic amides. This effort led to the discovery of potent BET inhibitors displaying overall improved profiles when compared to JQ1 and birabresib. A thiadiazole derived 1q (SJ1461) displayed excellent BRD4 and BRD2 affinity and high potency in the panel of acute leukaemia and medulloblastoma cell lines. A structure of 1q co-crystalised with BRD4-BD1 revealed polar interactions with the AZ/BC loops, in particular with Asn140 and Tyr139, rationalising the observed affinity improvements. In addition, exploration of pharmacokinetic properties of this class of compounds suggest that the heterocyclic amide moiety improves drug-like features. Our study led to the discovery of potent and orally bioavailable BET inhibitor 1q (SJ1461) as a promising candidate for further development.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ZR, MF, WCKP reports financial support was provided by ALSAC. VS reports financial support was provided by The Science Fund of The Republic of Serbia.
(Copyright © 2023 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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