2. Academic Validation
  3. Discovery and In Vivo Efficacy of AZ-PRMT5i-1, a Novel PRMT5 Inhibitor with High MTA Cooperativity

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

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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