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

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 <b>M1</b>, resulting from <i>N</i>-demethylation of lead inhibitor compound <b>12</b>, as a potent hERG inhibitor. Leveraging the kinetic isotope effect, we generated methyl-<i>d</i><sub>3</sub> analog <b>16</b> which reduced the formation of <b>M1</b> 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.

Authors

Institutions

Publication Details

Journal
Journal of Medicinal Chemistry
Published
2025-12-22
DOI
https://doi.org/10.1021/acs.jmedchem.5c02392
Primary Topic
Cancer-related gene regulation
Type
article
Field-Weighted Citation Impact
0.00
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

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

Radhakrishna Sura, Adam J. Schrier, Jessica Orf, Daniel E. Roa et al.
Journal of Medicinal Chemistry
Cancer-related gene regulation
article

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

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

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 <b>M1</b>, resulting from <i>N</i>-demethylation of lead inhibitor compound <b>12</b>, as a potent hERG inhibitor. Leveraging the kinetic isotope effect, we generated methyl-<i>d</i><sub>3</sub> analog <b>16</b> which reduced the formation of <b>M1</b> 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.

Journal of Medicinal ChemistryVol. 69(1)
UC Irvine Health (US), Gilead Sciences (United States) (US)
Good health and well-being
Openalex Percentile: Top 37%
Cancer-related gene regulation
DOISourceOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.