7NR5

Discovery of ASTX029, a clinical candidate which modulates the phosphorylation and catalytic activity of ERK1/2

Summary for 7NR5

• Entry DOI: 10.2210/pdb7nr5/pdb
• Related: 7NQQ 7NQW 7NR3
• Descriptor: Mitogen-activated protein kinase 1, SULFATE ION, (2~{R})-2-[5-[5-chloranyl-2-[(2-methyl-1,2,3-triazol-4-yl)amino]pyrimidin-4-yl]-3-oxidanylidene-1~{H}-isoindol-2-yl]-~{N}-[(1~{S})-1-(3-fluoranyl-5-methoxy-phenyl)-2-oxidanyl-ethyl]propanamide, ... (4 entities in total)
• Functional Keywords: serine/threonine kinase, signal transduction, map kinase, atp-binding protein, signaling protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 43517.17

Authors

O'Reilly, M.,Cleasby, A. (deposition date: 2021-03-03, release date: 2021-10-06, Last modification date: 2024-11-13)

Primary citation

Heightman, T.D.,Berdini, V.,Bevan, L.,Buck, I.M.,Carr, M.G.,Courtin, A.,Coyle, J.E.,Day, J.E.H.,East, C.,Fazal, L.,Griffiths-Jones, C.M.,Howard, S.,Kucia-Tran, J.,Martins, V.,Muench, S.,Munck, J.M.,Norton, D.,O'Reilly, M.,Palmer, N.,Pathuri, P.,Peakman, T.M.,Reader, M.,Rees, D.C.,Rich, S.J.,Shah, A.,Wallis, N.G.,Walton, H.,Wilsher, N.E.,Woolford, A.J.,Cooke, M.,Cousin, D.,Onions, S.,Shannon, J.,Watts, J.,Murray, C.W.
Discovery of ASTX029, A Clinical Candidate Which Modulates the Phosphorylation and Catalytic Activity of ERK1/2.
J.Med.Chem., 64:12286-12303, 2021

PubMed 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 () through structure-guided optimization of our previously published isoindolinone lead (). 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.

PubMed: 34387469
DOI: 10.1021/acs.jmedchem.1c00905

Experimental method

X-RAY DIFFRACTION (1.766 Å)