For research use only. Not for therapeutic Use.
GDC-0623（Cat No.:I000603）, also known as G-868, is a highly potent inhibitor of MEK1, a key kinase in the mitogen-activated protein kinase (MAPK) signaling pathway. It acts as an ATP-noncompetitive inhibitor, meaning it does not directly compete with ATP for binding to MEK1. GDC-0623 exhibits exceptional affinity for MEK1, with a Ki value of 0.13 nM. By selectively targeting and inhibiting MEK1, GDC-0623 has the potential to disrupt aberrant MAPK signaling in cancer cells, making it a promising candidate for the development of targeted cancer therapies.
| Catalog Number | I000603 |
| CAS Number | 1168091-68-6 |
| Synonyms | 5-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)imidazo[1,5-a]pyridine-6-carboxamide |
| Molecular Formula | C₁₆H₁₄FIN₄O₃ |
| Purity | ≥95% |
| Target | MEK1/2 |
| Solubility | DMSO: ≥ 30 mg/mL |
| Storage | Store at -20°C |
| IC50 | 0.13 nM (Ki, +ATP); 7 nM (EC50, A375 BRAF(V600E) ) |
| IUPAC Name | 5-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)imidazo[1,5-a]pyridine-6-carboxamide |
| InChI | InChI=1S/C16H14FIN4O3/c17-13-7-10(18)1-4-14(13)20-15-12(16(24)21-25-6-5-23)3-2-11-8-19-9-22(11)15/h1-4,7-9,20,23H,5-6H2,(H,21,24) |
| InChIKey | RFWVETIZUQEJEF-UHFFFAOYSA-N |
| SMILES | C1=CC(=C(C=C1I)F)NC2=C(C=CC3=CN=CN32)C(=O)NOCCO |
| Reference | 1:Drug Metab Dispos. 2015 Dec;43(12):1929-33. doi: 10.1124/dmd.115.067181. Epub 2015 Oct 5. Elucidating the Mechanisms of Formation for Two Unusual Cytochrome P450-Mediated Fused Ring Metabolites of GDC-0623, a MAPK/ERK Kinase Inhibitor.Takahashi RH,Ma S,Robinson SJ,Yue Q,Choo EF,Khojasteh SC, PMID: 26438627 DOI: 10.1124/dmd.115.067181 </br><span>Abstract:</span> Two isomeric metabolites of GDC-0623 [5-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)imidazo[1,5-a]pyridine-6-carboxamide], a mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) kinase inhibitor, were identified in radiolabeled mass balance studies in rats and dogs (approximately 5% in excreta) and were also observed in human circulation (nonradiolabeled). Mass spectrometric data indicated that both metabolites had formed a new ring structure fused to the imidazopyridine core. Given their unusual structures, we conducted experiments to elucidate their chemical structures and understand the mechanisms for their formation. For the first metabolite, M14, a pyrazol-3-ol ring was generated by N-N bond formation between the aniline and hydroxamate. For the second metabolite, M13, an imidazol-2-one was generated by a Hofmann-type rearrangement that involved C-C bond cleavage and C-N bond formation. Both reactions were catalyzed by CYP2C9 and CYP2C19. M14 was generated directly from GDC-0623 and we speculate that its formation was via oxidative activation of the hydroxamic ester by cytochrome P450 (P450) and intramolecular nucleophilic displacement of the ester side chain. M13 (the rearranged metabolite) formed from the N-reduced hydroxamate (amide) and not from GDC-0623 directly. We propose for M13 that a P450-mediated reaction formed a cationic amide intermediate, which enabled the molecular rearrangement of the imidazopyridine core migrating from the amide carbon to the nitrogen and subsequent cyclization reaction. Each of these metabolic pathways constitutes a novel biotransformation mediated by P450 enzymes. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics. |
