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

Tom D Heightman; Valerio Berdini; Luke Bevan; Ildiko M Buck; Maria G Carr; Aurélie Courtin; Joseph E Coyle; James E H Day; Charlotte East; Lynsey Fazal; Charlotte M Griffiths-Jones; Steven Howard; Justyna Kucia-Tran; Vanessa Martins; Sandra Muench; Joanne M Munck; David Norton; Marc O'Reilly; Nicholas Palmer; Puja Pathuri; Torren M Peakman; Michael Reader; David C Rees; Sharna J Rich; Alpesh Shah; Nicola G Wallis; Hugh Walton; Nicola E Wilsher; Alison J-A Woolford; Michael Cooke; David Cousin; Stuart Onions; Jonathan Shannon; John Watts; Christopher W Murray

doi:10.1021/acs.jmedchem.1c00905

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. Epub 2021 Aug 13.

Authors

Tom D Heightman¹, Valerio Berdini¹, Luke Bevan¹, Ildiko M Buck¹, Maria G Carr¹, Aurélie Courtin¹, Joseph E Coyle¹, James E H Day¹, Charlotte East¹, Lynsey Fazal¹, Charlotte M Griffiths-Jones¹, Steven Howard¹, Justyna Kucia-Tran¹, Vanessa Martins¹, Sandra Muench¹, Joanne M Munck¹, David Norton¹, Marc O'Reilly¹, Nicholas Palmer¹, Puja Pathuri¹, Torren M Peakman¹, Michael Reader¹, David C Rees¹, Sharna J Rich¹, Alpesh Shah¹, Nicola G Wallis¹, Hugh Walton¹, Nicola E Wilsher¹, Alison J-A Woolford¹, Michael Cooke², David Cousin², Stuart Onions², Jonathan Shannon², John Watts², Christopher W Murray¹

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.

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / metabolism
Antineoplastic Agents / pharmacokinetics
Antineoplastic Agents / therapeutic use*
Crystallography, X-Ray
Dogs
Humans
Indoles / chemical synthesis
Indoles / metabolism
Indoles / pharmacokinetics
Indoles / therapeutic use*
Male
Mice
Mice, Inbred BALB C
Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors*
Mitogen-Activated Protein Kinase 1 / chemistry
Mitogen-Activated Protein Kinase 1 / metabolism
Molecular Structure
Neoplasms / drug therapy*
Phosphorylation / drug effects
Protein Binding
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / metabolism
Protein Kinase Inhibitors / pharmacokinetics
Protein Kinase Inhibitors / therapeutic use*
Proto-Oncogene Mas
Pyrimidines / chemical synthesis
Pyrimidines / metabolism
Pyrimidines / pharmacokinetics
Pyrimidines / therapeutic use*
Rats
Rats, Sprague-Dawley
Rats, Wistar
Structure-Activity Relationship
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
Indoles
MAS1 protein, human
Protein Kinase Inhibitors
Proto-Oncogene Mas
Pyrimidines
Mitogen-Activated Protein Kinase 1