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

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.

• Authors: 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
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 64 Issue 16 Pg. 12286-12303 (08 26 2021) ISSN: 1520-4804 [Electronic] United States
• PMID: 34387469 (Publication Type: Journal Article)

Chemical References

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

Topics

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