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Discovery of TYRA-300: First Oral Selective FGFR3 Inhibitor for the Treatment of Urothelial Cancers and Achondroplasia.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2024 Sep 26; Vol. 67 (18), pp. 16737-16756. Date of Electronic Publication: 2024 Sep 11. - Publication Year :
- 2024
-
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 ( 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.
- Subjects :
- Humans
Animals
Antineoplastic Agents pharmacology
Antineoplastic Agents chemistry
Antineoplastic Agents therapeutic use
Administration, Oral
Structure-Activity Relationship
Protein Kinase Inhibitors pharmacology
Protein Kinase Inhibitors chemistry
Protein Kinase Inhibitors therapeutic use
Rats
Drug Discovery
Receptor, Fibroblast Growth Factor, Type 3 antagonists & inhibitors
Receptor, Fibroblast Growth Factor, Type 3 metabolism
Receptor, Fibroblast Growth Factor, Type 3 genetics
Achondroplasia drug therapy
Urinary Bladder Neoplasms drug therapy
Urinary Bladder Neoplasms pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 67
- Issue :
- 18
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 39258897
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.4c01531