Clobetasol Propionate Is a Heme-Mediated Selective Inhibitor of Human Cytochrome P450 3A5.

Autor:	Wright WC; Department of Chemical Biology and Therapeutics , St. Jude Children's Research Hospital , Memphis , Tennessee 38105-3678 , United States.; Integrated Biomedical Sciences Program , University of Tennessee Health Science Center , Memphis , Tennessee 38163 , United States., Chenge J; Department of Chemical Biology and Therapeutics , St. Jude Children's Research Hospital , Memphis , Tennessee 38105-3678 , United States., Wang J; Department of Chemical Biology and Therapeutics , St. Jude Children's Research Hospital , Memphis , Tennessee 38105-3678 , United States., Girvan HM; Manchester Institute of Biotechnology, School of Natural Sciences, Department of Chemistry , The University of Manchester , Manchester M1 7DN , U.K., Yang L; Department of Chemical Biology and Therapeutics , St. Jude Children's Research Hospital , Memphis , Tennessee 38105-3678 , United States., Chai SC; Department of Chemical Biology and Therapeutics , St. Jude Children's Research Hospital , Memphis , Tennessee 38105-3678 , United States., Huber AD; Department of Chemical Biology and Therapeutics , St. Jude Children's Research Hospital , Memphis , Tennessee 38105-3678 , United States., Wu J; Department of Chemical Biology and Therapeutics , St. Jude Children's Research Hospital , Memphis , Tennessee 38105-3678 , United States., Oladimeji PO; Department of Chemical Biology and Therapeutics , St. Jude Children's Research Hospital , Memphis , Tennessee 38105-3678 , United States., Munro AW; Manchester Institute of Biotechnology, School of Natural Sciences, Department of Chemistry , The University of Manchester , Manchester M1 7DN , U.K., Chen T; Department of Chemical Biology and Therapeutics , St. Jude Children's Research Hospital , Memphis , Tennessee 38105-3678 , United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2020 Feb 13; Vol. 63 (3), pp. 1415-1433. Date of Electronic Publication: 2020 Jan 22.
DOI:	10.1021/acs.jmedchem.9b02067
Abstrakt:	The human cytochrome P450 (CYP) enzymes CYP3A4 and CYP3A5 metabolize most drugs and have high similarities in their structure and substrate preference. Whereas CYP3A4 is predominantly expressed in the liver, CYP3A5 is upregulated in cancer, contributing to drug resistance. Selective inhibitors of CYP3A5 are, therefore, critical to validating it as a therapeutic target. Here we report clobetasol propionate (clobetasol) as a potent and selective CYP3A5 inhibitor identified by high-throughput screening using enzymatic and cell-based assays. Molecular dynamics simulations suggest a close proximity of clobetasol to the heme in CYP3A5 but not in CYP3A4. UV-visible spectroscopy and electron paramagnetic resonance analyses confirmed the formation of an inhibitory type I heme-clobetasol complex in CYP3A5 but not in CYP3A4, thus explaining the CYP3A5 selectivity of clobetasol. Our results provide a structural basis for selective CYP3A5 inhibition, along with mechanistic insights, and highlight clobetasol as an important chemical tool for target validation.
Databáze:	MEDLINE
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