Discovery of ASTX029, A Clinical Candidate Which Modulates the Phosphorylation and Catalytic Activity of ERK1/2

  • J Med Chem. 2021 Aug 26;64(16):12286-12303. doi: 10.1021/acs.jmedchem.1c00905.
Tom D Heightman  1 ,  Valerio Berdini  1 ,  Luke Bevan  1 ,  Ildiko M Buck  1 ,  Maria G Carr  1 ,  Aurélie Courtin  1 ,  Joseph E Coyle  1 ,  James E H Day  1 ,  Charlotte East  1 ,  Lynsey Fazal  1 ,  Charlotte M Griffiths-Jones  1 ,  Steven Howard  1 ,  Justyna Kucia-Tran  1 ,  Vanessa Martins  1 ,  Sandra Muench  1 ,  Joanne M Munck  1 ,  David Norton  1 ,  Marc O'Reilly  1 ,  Nicholas Palmer  1 ,  Puja Pathuri  1 ,  Torren M Peakman  1 ,  Michael Reader  1 ,  David C Rees  1 ,  Sharna J Rich  1 ,  Alpesh Shah  1 ,  Nicola G Wallis  1 ,  Hugh Walton  1 ,  Nicola E Wilsher  1 ,  Alison J-A Woolford  1 ,  Michael Cooke  2 ,  David Cousin  2 ,  Stuart Onions  2 ,  Jonathan Shannon  2 ,  John Watts  2 ,  Christopher W Murray  1
Affiliations
  • 1. Astex Pharmaceuticals, 436 Cambridge Science Park, Cambridge CB4 0QA, U.K.
  • 2. Sygnature Discovery Ltd., BioCity, Pennyfoot Street, Nottingham NG1 1GF, U.K.
PMID: 34387469 DOI: 10.1021/acs.jmedchem.1c00905
Abstract

Aberrant activation of the mitogen-activated protein kinase pathway frequently drives tumor growth, and the ERK1/2 kinases are positioned at a key node in this pathway, making them important targets for therapeutic intervention. Recently, a number of ERK1/2 inhibitors have been advanced to investigational clinical trials in patients with activating mutations in B-Raf proto-oncogene or Ras. Here, we describe the discovery of the clinical candidate ASTX029 (15) through structure-guided optimization of our previously published isoindolinone lead (7). The medicinal chemistry campaign focused on addressing CYP3A4-mediated metabolism and maintaining favorable physicochemical properties. These efforts led to the identification of ASTX029, which showed the desired pharmacological profile combining ERK1/2 inhibition with suppression of phospho-ERK1/2 (PERK) levels, and in addition, it possesses suitable preclinical pharmacokinetic properties predictive of once daily dosing in humans. ASTX029 is currently in a phase I-II clinical trial in patients with advanced solid tumors.