8UDV

The X-RAY co-crystal structure of human FGFR3 V555M and Compound 17

Summary for 8UDV

• Entry DOI: 10.2210/pdb8udv/pdb
• Related: 8UDT 8UDU
• Descriptor: Fibroblast growth factor receptor 3, SULFATE ION, 3-[(6-chloro-1-cyclopropyl-1H-benzimidazol-5-yl)ethynyl]-1-[(3S,5S)-5-(methoxymethyl)-1-(prop-2-enoyl)pyrrolidin-3-yl]-5-(methylamino)-1H-pyrazole-4-carboxamide, ... (5 entities in total)
• Functional Keywords: fgfr inhibitor, covalent drug, kin-3248, alteration, mutation, structure-based drug design, kinase inhibitor, signaling, proliferation, transferase, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 3
• Total formula weight: 103628.79

Authors

Tyhonas, J.S.,Arnold, L.D.,Cox, J.,Franovic, A.,Gardiner, E.,Grandinetti, K.,Kania, R.,Kanouni, T.,Lardy, M.,Li, C.,Martin, E.S.,Miller, N.,Mohan, A.,Murphy, E.A.,Perez, M.,Soroceanu, L.,Timple, N.,Uryu, S.,Womble, S.,Kaldor, S.W. (deposition date: 2023-09-29, release date: 2024-02-07, Last modification date: 2024-10-30)

Primary citation

Tyhonas, J.S.,Arnold, L.D.,Cox, J.M.,Franovic, A.,Gardiner, E.,Grandinetti, K.,Kania, R.,Kanouni, T.,Lardy, M.,Li, C.,Martin, E.S.,Miller, N.,Mohan, A.,Murphy, E.A.,Perez, M.,Soroceanu, L.,Timple, N.,Uryu, S.,Womble, S.,Kaldor, S.W.
Discovery of KIN-3248, An Irreversible, Next Generation FGFR Inhibitor for the Treatment of Advanced Tumors Harboring FGFR2 and/or FGFR3 Gene Alterations.
J.Med.Chem., 67:1734-1746, 2024

PubMed Abstract: Fibroblast growth factor receptor (FGFR) alterations are present as oncogenic drivers and bypass mechanisms in many forms of cancer. These alterations can include fusions, amplifications, rearrangements, and mutations. Acquired drug resistance to current FGFR inhibitors often results in disease progression and unfavorable outcomes for patients. Genomic profiling of tumors refractory to current FGFR inhibitors in the clinic has revealed several acquired driver alterations that could be the target of next generation therapeutics. Herein, we describe how structure-based drug design (SBDD) was used to enable the discovery of the potent and kinome selective pan-FGFR inhibitor , which is active against many acquired resistance mutations. is currently in phase I clinical development for the treatment of advanced tumors harboring FGFR2 and/or FGFR3 gene alterations.

PubMed: 38267212
DOI: 10.1021/acs.jmedchem.3c01819

Experimental method

X-RAY DIFFRACTION (2.348 Å)