8E1X

FGFR2 kinase domain in complex with a Pyrazolo[1,5-a]pyrimidine analog (Compound 29)

Summary for 8E1X

• Entry DOI: 10.2210/pdb8e1x/pdb
• Descriptor: Fibroblast growth factor receptor 2, (5M)-N-methyl-5-{(6M,8S)-5-{[(3S)-oxolan-3-yl]amino}-6-[1-(propan-2-yl)-1H-pyrazol-3-yl]pyrazolo[1,5-a]pyrimidin-3-yl}pyridine-3-carboxamide (3 entities in total)
• Functional Keywords: fgfr, inhibitor, kinase, gatekeeper, hyperphosphatemia, structural protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 76539.42

Authors

Lei, H.-T.,Epling, L.B.,Deller, M.C. (deposition date: 2022-08-11, release date: 2022-11-23, Last modification date: 2024-11-20)

Primary citation

Shvartsbart, A.,Roach, J.J.,Witten, M.R.,Koblish, H.,Harris, J.J.,Covington, M.,Hess, R.,Lin, L.,Frascella, M.,Truong, L.,Leffet, L.,Conlen, P.,Beshad, E.,Klabe, R.,Katiyar, K.,Kaldon, L.,Young-Sciame, R.,He, X.,Petusky, S.,Chen, K.J.,Horsey, A.,Lei, H.T.,Epling, L.B.,Deller, M.C.,Vechorkin, O.,Yao, W.
Discovery of Potent and Selective Inhibitors of Wild-Type and Gatekeeper Mutant Fibroblast Growth Factor Receptor (FGFR) 2/3.
J.Med.Chem., 65:15433-15442, 2022

PubMed Abstract: Upregulation of the fibroblast growth factor receptor (FGFR) signaling pathway has been implicated in multiple cancer types, including cholangiocarcinoma and bladder cancer. Consequently, small molecule inhibition of FGFR has emerged as a promising therapy for patients suffering from these diseases. First-generation pan-FGFR inhibitors, while highly effective, suffer from several drawbacks. These include treatment-related hyperphosphatemia and significant loss of potency for the mutant kinases. Herein, we present the discovery and optimization of novel FGFR2/3 inhibitors that largely maintain potency for the common gatekeeper mutants and have excellent selectivity over FGFR1. A combination of meticulous structure-activity relationship (SAR) analysis, structure-based drug design, and medicinal chemistry rationale ultimately led to compound , a potent and selective FGFR2/3 inhibitor with excellent absorption, distribution, metabolism, excretion (ADME), and pharmacokinetics in rat. A pharmacodynamic study of a closely related compound established that maximum inhibition of downstream ERK phosphorylation could be achieved with no significant effect on serum phosphate levels relative to vehicle.

PubMed: 36356320
DOI: 10.1021/acs.jmedchem.2c01366

Experimental method

X-RAY DIFFRACTION (2.68 Å)