9CD7

FGFR3 Kinase Domain with Inhibitor TYRA-300

This is a non-PDB format compatible entry.

Summary for 9CD7

• Entry DOI: 10.2210/pdb9cd7/pdb
• Descriptor: Fibroblast growth factor receptor 3, (3P)-5-[(1R)-1-(3,5-dichloropyridin-4-yl)ethoxy]-3-{6-[6-(methanesulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl]pyridin-3-yl}-1H-indazole, GLYCEROL, ... (5 entities in total)
• Functional Keywords: kinase, transferase, inhibitor, cancer, achondroplasia, fgfr3, fgfr, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 3
• Total formula weight: 108858.23

Authors

Hoffman, I.H.,Nelson, K.J.,Rideout, M.C.,Nix, J.C.,Frye, C.,Bensen, D.C.,Hudkins, R.L. (deposition date: 2024-06-24, release date: 2024-09-25, Last modification date: 2024-10-02)

Primary citation

Hudkins, R.L.,Allen, E.,Balcer, A.,Hoffman, I.D.,Iyer, S.,Neal, M.,Nelson, K.J.,Rideout, M.,Ye, Q.,Starrett, J.H.,Patel, P.,Harris, T.,Swanson, R.V.,Bensen, D.C.
Discovery of TYRA-300: First Oral Selective FGFR3 Inhibitor for the Treatment of Urothelial Cancers and Achondroplasia.
J.Med.Chem., 67:16737-16756, 2024

PubMed Abstract: Activating FGFR3 alterations have been identified in up to 15-20% of muscle-invasive bladder cancer and metastatic urothelial carcinoma (mUC), and as high as 80% in nonmuscle invasive bladder cancers. FGFR3 germline mutations have also been associated with a variety of skeletal dysplasias. Achondroplasia, the most common form of dwarfism in humans, results from a G380R mutation in FGFR3. The pan-FGFR inhibitor erdafitinib was approved for the treatment of mUC with FGFR3 alterations but is limited due to FGFR isoform off-target toxicities and the development of on-target gatekeeper resistance mutations. TYRA-300 () was conceived using a structure-based approach as a potent FGFR3-selective inhibitor to avoid the toxicities associated with inhibition of FGFR1, FGFR2, and FGFR4, and to be agnostic for the FGFR3 gatekeeper mutations. TYRA-300 is being evaluated in a Phase 1 clinical trial in urothelial cancers and solid tumors, with intention to initiate Phase 2 studies in urothelial cancers and achondroplasia.

PubMed: 39258897
DOI: 10.1021/acs.jmedchem.4c01531

Experimental method

X-RAY DIFFRACTION (2.53 Å)