Controlling Ibrutinib's Conformations about Its Heterobiaryl Axis to Increase BTK Selectivity.

Autor:	Toenjes ST; Department of Chemistry and Biochemistry and Donald P. Shiley BioScience Center, San Diego State University, San Diego, California 92182-1030, United States., Heydari BS; Department of Chemistry and Biochemistry and Donald P. Shiley BioScience Center, San Diego State University, San Diego, California 92182-1030, United States., Albright ST; Department of Chemistry and Biochemistry and Donald P. Shiley BioScience Center, San Diego State University, San Diego, California 92182-1030, United States., Hazin R; Department of Chemistry and Biochemistry and Donald P. Shiley BioScience Center, San Diego State University, San Diego, California 92182-1030, United States., Ortiz MA; Department of Chemistry and Biochemistry and Donald P. Shiley BioScience Center, San Diego State University, San Diego, California 92182-1030, United States., Piedrafita FJ; Department of Chemistry and Biochemistry and Donald P. Shiley BioScience Center, San Diego State University, San Diego, California 92182-1030, United States., Gustafson JL; Department of Chemistry and Biochemistry and Donald P. Shiley BioScience Center, San Diego State University, San Diego, California 92182-1030, United States.
Jazyk:	angličtina
Zdroj:	ACS medicinal chemistry letters [ACS Med Chem Lett] 2023 Feb 14; Vol. 14 (3), pp. 305-311. Date of Electronic Publication: 2023 Feb 14 (Print Publication: 2023).
DOI:	10.1021/acsmedchemlett.2c00523
Abstrakt:	Ibrutinib is a covalent BTK inhibitor that is approved for several indications in oncology. Ibrutinib possesses significant off-target activities toward many kinases, often leading to adverse events in patients. While there have been robust medicinal chemistry efforts leading to more selective second-generation BTK inhibitors, there remains a need for new strategies to rapidly improve the selectivity of kinase inhibitors. An analysis of PDB data revealed that ibrutinib binds BTK in dihedral conformations that are orthogonal of ibrutinib's predicted low energy conformational range. Synthesis of a series of analogues with ground state conformations shifted toward orthogonality led to the discovery of an analogue with two incorporated ortho -methyl groups that possessed markedly increased BTK selectivity. This work suggests that conformational control about a prospective atropisomeric axis represents a strategy to rapidly program a compound's selectivity toward a given target. Competing Interests: The authors declare no competing financial interest. (© 2023 The Authors. Published by American Chemical Society.)
Databáze:	MEDLINE
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