LC-MB12 is an orally active PROTAC compound targets FGFR2 degradation with a DC50 of 11.8 nM. LC-MB12 contains BGJ398 (a FGFR2 inhibitor), PROTAC linker and CRBN.LC-MB12 inhibits FGFR2 signaling in gastric cancer cells and has anti-tumor activity.
LC-MB12 (0.5-10,000 nM, 3-12 hours) degrades FGFR2 in a time-dependent manner in KATO III, with a DC50 of 11.8 nM.LC-MB12 (100 nM, 6 hours) degrades FGFR2 to 77% in KATO III and 43% in NCI-H1581[1].LC-MB12 (1-10000 nM, 72 hours) inhibits the growth of KATO III, SNU-16, and NCI-H716 significantly with IC50s of 29.1 nM, 3.7 nM and 3.2 nM, respectively, and induces KATO III G0/G1 phase arrest[1].
LC-MB12 (20 mg/kg/day, p.o., 15 days) inhibits tumor growth to 63.1% in SNU-16 xenograft models of nude mice[1].LC-MB12 (20 mg/kg, p.o.) shows fast absorption (Cmax: 2.6 h) and orally bioavailable (F: 13%) in mice[1].LC-MB12 (20 mg/kg, p.o., 30 days) is well tolerated and has no apparent hepatotoxicity or nephrotoxicity in mice[1].In Vivo PK Properties of LC-MB12[1]
References:
[1]. Ma L, et al. Discovery of a Selective and Orally Bioavailable FGFR2 Degrader for Treating Gastric Cancer. J Med Chem. 2023 Jun 8;66(11):7438-7453.