Discovery of TYRA-300: First Oral Selective FGFR3 Inhibitor for the Treatment of Urothelial Cancers and Achondroplasia

• Published in: Journal of medicinal chemistry Vol. 67; no. 18; pp. 16737 - 16756
• Main Authors: Hudkins, Robert L., Allen, Eric, Balcer, Alexandra, Hoffman, Isaac D., Iyer, Samhita, Neal, Melissa, Nelson, Kirk J., Rideout, Marc, Ye, Qing, Starrett, Jacqueline H., Patel, Piyush, Harris, Todd, Swanson, Ronald V., Bensen, Daniel C.
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 26.09.2024
• Subjects: Achondroplasia - drug therapy; Administration, Oral; Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Drug Discovery; Humans; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Rats; Receptor, Fibroblast Growth Factor, Type 3 - antagonists & inhibitors; Receptor, Fibroblast Growth Factor, Type 3 - genetics; Receptor, Fibroblast Growth Factor, Type 3 - metabolism; Structure-Activity Relationship; Urinary Bladder Neoplasms - drug therapy; Urinary Bladder Neoplasms - pathology
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.4c01531

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 (22) 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.