posted on 2021-08-26, 07:30authored byTom 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
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.