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

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

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.

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