KG-FP-003

KG-FP-003 is a highly effective, selective, and durable TEAD PROTAC degrader featuring degradation concentrations of TEAD1DC50= 6 ± 4 nM, TEAD2DC50= 68 ± 15 nM, TEAD3DC50= 12 ± 5 nM, and TEAD4DC50= 7 ± 5 nM. It facilitates the ubiquitination and degradation of TEAD and exhibits anticancer activity against mesothelioma and ovarian cancer.

TEAD1:6 nM (DC50)

KG-FP-003 binds to the recombinant CRBN-DDB1ΔBPB protein with an IC50 of 591 ± 21 nM. In an experiment where KG-FP-003 was applied at a concentration of 10 μM with a threefold serial dilution for 2 hours, the compound bound to CRBN in HEK293T cells overexpressing NanoLuc-CRBN, yielding an IC50 of 962 ± 86 nM in a cellular binding assay. When HEK293T cells tagged with HiBiT were treated for 6 hours, KG-FP-003 selectively degraded all four TEAD isoforms effectively, with DC50 values of TEAD1 at 6 ± 4 nM, TEAD2 at 68 ± 15 nM, TEAD3 at 12 ± 5 nM, and TEAD4 at 7 ± 5 nM. Additionally, a 72-hour treatment with KG-FP-003 strongly inhibited the proliferation of NCI-H226 mesothelioma cells, achieving an IC50 of 27 ± 7 nM.

KG-FP-003, administered via intraperitoneal injection once daily for 21 consecutive days at doses ranging from 3 to 30 mg/kg, exhibits significant dose-dependent antitumor activity in the NF2-deficient MSTO-211H mesothelioma xenograft model. Additionally, at doses of 10 mg/kg and 30 mg/kg, KG-FP-003 effectively induces regression of ES2 ovarian cancer xenograft tumors.