RET high selective inhibitor

1. The urgent need of RET G810-mut inhibitor.

(1) RET is activated by RET mutations and fusions in several cancers, including thyroid, lung, breast and colon carcinoma.

(2) Pralsetinib and Selpercatinib are effective against the RET V804L/M gatekeeper mutants. However, adaptive mutations that cause resistance at the solvent front RET G810 residue have been found, pointing to the need for the development of the next-generation of RET-specific TKIs.

(3) It is urgent to develop RET inhibitor against the solvent front mutation RET G810, developed as on-target resistance to selpercatinib and pralsetinib.

2. High selective RET inhibitor.

Selectivity at the cellular level shows: The asset > 10-fold selective vs. FGFR2 and > 30-fold selective vs. VEGFR2, FGFR1, FGFR3-4, KIT and FLT3.

3. Excellent RET inhibitory activity in vivo.

(1) The anti-tumor effect of the asset is better than that of LOXO-292 in patient-derived human RET fusion colorectal cancer model intracranially implanted in nude mice.

(2) Asset showed higher concentration in brain tissue comparing to LOXO-292 in vivo.

(3) The anti-tumor effect is significantly better than LOXO-292 in BAF3-KIF5B-RET-G810S tumor allografts and intracranial tumor Xenograft.

4. Good safety

(1) The margin of exposure of the asset reaches approximately 64 times estimated with MRHD, and approximately 714 times estimated with the pharmacodynamics model.

(2) hERG IC50>10 μM, lower risk of prolongation of QT interval.

(3) No abnormality was observed in the cardiovascular, respiratory and central nervous systems.

(4) No genotoxicity.