Discovery of ASTX029, A Clinical Candidate Which Modulates the Phosphorylation and Catalytic Activity of ERK1/2
Tom D. Heightman, Valério Berdini, Luke Bevan, Ildiko M. Buck, Maria G. Carr, Aurélie Courtin, Joseph E. Coyle, James E. H. Day, Charlotte East, Lynsey Fazal, Charlotte Griffiths-Jones, Steven Howard, Justyna Kucia-Tran, Vanessa Martins, Sandra Muench, Joanne M. Munck, David L. Norton, Marc O’Reilly, Nicholas J. 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, M. Cooke, David Cousin, Stuart Onions, Jonathan Shannon, John W. Watts, Christopher W. Murray
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.