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

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

  • J Med Chem. 2026 Jan 8;69(1):289-304. doi: 10.1021/acs.jmedchem.5c02392.
Laurent Debien 1,  Megan K Armstrong 1,  Joshua D Farr 1,  Ryan D Ferrao 1,  Pancham Lal Gupta 1,  Congrong Niu 1,  Andrew J Anderson 1,  Phillip Benner 1,  Ashleigh N Bristol 1,  Elbert Chin 1,  Chienhung Chou 1,  Yifan Deng 1,  Xiaoyong Fu 1,  Mina Gheiratmand 1,  Sarah M Hull 1,  Joey Chao-I Hung 1,  Ben June 1,  Jung Hwa Kirschman 1,  Hoa Le 1,  Bhavna Malik 1,  Michael L Mitchell 1,  Prasenjit Kumar Mukherjee 1,  Shaina V Nguyen 2,  Gregory T Notte 1,  Jessica Orf 1,  Daniel E Roa 1,  Rex Santos 1,  Adam J Schrier 1,  Katie A Spence 1,  Radhakrishna Sura 1,  Zheng-Yu Yang 1,  Doris Zane 1,  Ariel N Zahabian 1,  Tatiana Zavorotinskaya 1
Affiliations

Affiliations

  • 1 Gilead Sciences Inc., Foster City, California 94404, United States.
  • 2 UC Irvine, Irvine, California 92697, United States.
PMID: 41429045 DOI: 10.1021/acs.jmedchem.5c02392
Abstract

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.

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