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==Discovery of ASTX029, a clinical candidate which modulates the phosphorylation and catalytic activity of ERK1/2== | ==Discovery of ASTX029, a clinical candidate which modulates the phosphorylation and catalytic activity of ERK1/2== | ||
<StructureSection load='7nr8' size='340' side='right'caption='[[7nr8]]' scene=''> | <StructureSection load='7nr8' size='340' side='right'caption='[[7nr8]], [[Resolution|resolution]] 1.63Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7NR8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7NR8 FirstGlance]. <br> | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7NR8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7NR8 FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7nr8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7nr8 OCA], [https://pdbe.org/7nr8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7nr8 RCSB], [https://www.ebi.ac.uk/pdbsum/7nr8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7nr8 ProSAT]</span></td></tr> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.627Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CME:S,S-(2-HYDROXYETHYL)THIOCYSTEINE'>CME</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=UOE:(2~{R})-2-[5-[5-chloranyl-2-(oxan-4-ylamino)pyrimidin-4-yl]-3-oxidanylidene-1~{H}-isoindol-2-yl]-~{N}-[(1~{S})-1-[6-(4-methylpiperazin-1-yl)pyridin-2-yl]-2-oxidanyl-ethyl]propanamide'>UOE</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7nr8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7nr8 OCA], [https://pdbe.org/7nr8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7nr8 RCSB], [https://www.ebi.ac.uk/pdbsum/7nr8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7nr8 ProSAT]</span></td></tr> | |||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
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. | |||
Discovery of ASTX029, A Clinical Candidate Which Modulates the Phosphorylation and Catalytic Activity of ERK1/2.,Heightman TD, Berdini V, Bevan L, Buck IM, Carr MG, Courtin A, Coyle JE, Day JEH, East C, Fazal L, Griffiths-Jones CM, Howard S, Kucia-Tran J, Martins V, Muench S, Munck JM, Norton D, O'Reilly M, Palmer N, Pathuri P, Peakman TM, Reader M, Rees DC, Rich SJ, Shah A, Wallis NG, Walton H, Wilsher NE, Woolford AJ, Cooke M, Cousin D, Onions S, Shannon J, Watts J, Murray CW J Med Chem. 2021 Aug 26;64(16):12286-12303. doi: 10.1021/acs.jmedchem.1c00905., Epub 2021 Aug 13. PMID:34387469<ref>PMID:34387469</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7nr8" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Mitogen-activated protein kinase 3D structures|Mitogen-activated protein kinase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
Latest revision as of 14:15, 23 October 2024
Discovery of ASTX029, a clinical candidate which modulates the phosphorylation and catalytic activity of ERK1/2Discovery of ASTX029, a clinical candidate which modulates the phosphorylation and catalytic activity of ERK1/2
Structural highlights
Publication Abstract from PubMedAberrant 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. Discovery of ASTX029, A Clinical Candidate Which Modulates the Phosphorylation and Catalytic Activity of ERK1/2.,Heightman TD, Berdini V, Bevan L, Buck IM, Carr MG, Courtin A, Coyle JE, Day JEH, East C, Fazal L, Griffiths-Jones CM, Howard S, Kucia-Tran J, Martins V, Muench S, Munck JM, Norton D, O'Reilly M, Palmer N, Pathuri P, Peakman TM, Reader M, Rees DC, Rich SJ, Shah A, Wallis NG, Walton H, Wilsher NE, Woolford AJ, Cooke M, Cousin D, Onions S, Shannon J, Watts J, Murray CW J Med Chem. 2021 Aug 26;64(16):12286-12303. doi: 10.1021/acs.jmedchem.1c00905., Epub 2021 Aug 13. PMID:34387469[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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