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

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.