Discovery and In Vivo Efficacy of AZ-PRMT5i-1, a Novel PRMT5 Inhibitor with High MTA Cooperativity

  • J Med Chem. 2024 Aug 22;67(16):13604-13638. doi: 10.1021/acs.jmedchem.4c00097.
James M Smith  1 ,  Bernard Barlaam  1 ,  David Beattie  1 ,  Lauren Bradshaw  1 ,  Ho Man Chan  2 ,  Elisabetta Chiarparin  1 ,  Olga Collingwood  1 ,  Sophie L Cooke  1 ,  Anna Cronin  1 ,  Iain Cumming  1 ,  Emma Dean  1 ,  Judit É Debreczeni  3 ,  Iván Del Barco Barrantes  1 ,  Coura Diene  1 ,  Davide Gianni  3 ,  Carine Guerot  1 ,  Xiaoxiao Guo  3 ,  Sinem Guven  1 ,  Thomas G Hayhow  1 ,  Ted Hong  2 ,  Paul D Kemmitt  1 ,  Gillian M Lamont  1 ,  Scott Lamont  1 ,  James T Lynch  1 ,  Lisa McWilliams  3 ,  Shaun Moore  1 ,  Piotr Raubo  1 ,  Graeme R Robb  1 ,  James Robinson  3 ,  James S Scott  1 ,  Bharath Srinivasan  3 ,  Oliver Steward  1 ,  Christopher J Stubbs  3 ,  Karl Syson  3 ,  Lixiang Tan  4 ,  Oliver Turner  1 ,  Elizabeth Underwood  3 ,  Jelena Urosevic  1 ,  Mercedes Vazquez-Chantada  3 ,  Amy L Whittaker  3 ,  David M Wilson  1 ,  Jon J Winter-Holt  1
Affiliations
  • 1. Research and Early Development, Oncology R&D, AstraZeneca, Cambridge CB2 0AA, United Kingdom.
  • 2. Research and Early Development, Oncology R&D, AstraZeneca, Waltham 02451, United States.
  • 3. Discovery Sciences, Biopharmaceuticals R&D, AstraZeneca, Cambridge CB2 0AA, United Kingdom.
  • 4. Pharmaron Beijing Company, Ltd., Beijing 100176, P. R. China.
PMID: 39080842 DOI: 10.1021/acs.jmedchem.4c00097
Abstract

PRMT5, a type 2 arginine methyltransferase, has a critical role in regulating cell growth and survival in Cancer. With the aim of developing MTA-cooperative PRMT5 inhibitors suitable for MTAP-deficient cancers, herein we report our efforts to develop novel "MTA-cooperative" compounds identified through a high-throughput biochemical screening approach. Optimization of hits was achieved through structure-based design with a focus on improvement of oral drug-like properties. Bioisosteric replacement of the original thiazole guanidine headgroup, spirocyclization of the isoindolinone amide scaffold to both configurationally and conformationally lock the bioactive form, and fine-tuning of the potency, MTA cooperativity, and DMPK properties through specific substitutions of the azaindole headgroup were conducted. We have identified an orally available in vivo lead compound, 28 ("AZ-PRMT5i-1"), which shows sub-10 nM PRMT5 cell potency, >50-fold MTA cooperativity, suitable DMPK properties for oral dosing, and significant PRMT5-driven in vivo efficacy in several MTAP-deficient preclinical Cancer models.

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