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DOI 10.1021/acs.jmedchem.5c02392

Медицинская библиотека · Journal of medicinal chemistry · 2025

Discovery of Bis-Acyl Hydrazides as Potent and Bioavailable MTA-Cooperative PRMT5 Inhibitors: A Case Study of Leveraging the Deuterium Kinetic Isotope Effect.

Debien Laurent, Armstrong Megan K, Farr Joshua D, Ferrao Ryan D, Gupta Pancham Lal, Niu Congrong, Anderson Andrew J, Benner Phillip, Bristol Ashleigh N, Chin Elbert, Chou Chienhung, Deng Yifan, Fu Xiaoyong, Gheiratmand Mina, Hull Sarah M, Hung Joey Chao-I, June Ben, Kirschman Jung Hwa, Le Hoa, Malik Bhavna, Mitchell Michael L, Mukherjee Prasenjit Kumar, Nguyen Shaina V, Notte Gregory T, Orf Jessica, Roa Daniel E, Santos Rex, Schrier Adam J, Spence Katie A, Sura Radhakrishna, Yang Zheng-Yu, Zane Doris, Zahabian Ariel N, Zavorotinskaya Tatiana

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Аннотация

We describe the discovery of a series of potent, selective, and orally bioavailable bis-acyl hydrazide inhibitors targeting the PRMT5·MTA complex for the treatment of MTAP-deleted cancers. Key to this discovery was the identification of major metabolite M1, resulting from N-demethylation of lead inhibitor compound 12, as a potent hERG inhibitor. Leveraging the kinetic isotope effect, we generated methyl-d3 analog 16 which reduced the formation of M1 in vivo, resulting in acceptable safety margins and an improved pharmacokinetic profile. Our data suggest this strategy could be employed more broadly to reduce undesirable metabolism of methylated amines.

Для цитирования: Debien Laurent, Armstrong Megan K, Farr Joshua D, Ferrao Ryan D, Gupta Pancham Lal, Niu Congrong, Anderson Andrew J, Benner Phillip, Bristol Ashleigh N, Chin Elbert, Chou Chienhung, Deng Yifan, Fu Xiaoyong, Gheiratmand Mina, Hull Sarah M, Hung Joey Chao-I, June Ben, Kirschman Jung Hwa, Le Hoa, Malik Bhavna, Mitchell Michael L, Mukherjee Prasenjit Kumar, Nguyen Shaina V, Notte Gregory T, Orf Jessica, Roa Daniel E, Santos Rex, Schrier Adam J, Spence Katie A, Sura Radhakrishna, Yang Zheng-Yu, Zane Doris, Zahabian Ariel N, Zavorotinskaya Tatiana. Discovery of Bis-Acyl Hydrazides as Potent and Bioavailable MTA-Cooperative PRMT5 Inhibitors: A Case Study of Leveraging the Deuterium Kinetic Isotope Effect.. Journal of medicinal chemistry. 2025. DOI: 10.1021/acs.jmedchem.5c02392.

Предметные рубрики MeSH

HumansProtein-Arginine N-MethyltransferasesHydrazinesAnimalsDeuteriumStructure-Activity RelationshipKineticsEnzyme InhibitorsBiological AvailabilityDrug DiscoveryRatsMice
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