PROTACRIPK1Degrader-1 is a selective RIPK1 PROTAC degrader. This compound degrades RIPK1 in various cancer cell lines, such as A375 and B16F10 cells. It enhances the anticancer effects of radiotherapy in both syngeneic and humanized mouse models. PROTACRIPK1Degrader-1 is applicable for research in cancers like melanoma.

PROTAC RIPK1 Degrader-1 (Compound 225-5) effectively induces the degradation of RIPK1 in various cell lines such as HEK-293T-RIPK1-HiBiT (DC 50 < 0.1 nM, Dmax = 93%), A375 (DC 50 = 41 nM, Dmax = 97%), B16F10 (DC 50 = 91 nM, Dmax = 92%), as well as PC3, LNCap, MCF7, NOMO1, RS4;11, and U87, by binding to RIPK1, VHL, the proteasome, and the Cullin-RING E3 ligase complex. The effective concentration range is 0-1 μM over 1-20 hours.

PROTAC RIPK1 Degrader-1 (Compound 225-5), administered at 10-50 mg/kg via intraperitoneal or intravenous injection twice or once daily for 3-11 days, reduces RIPK1 levels in B16F10 C57BL/6 mouse models. Additionally, PROTAC RIPK1 Degrader-1 at 10-20 mg/kg through intraperitoneal injection once daily for 3-11 days lowers RIPK1 levels in humanized A375 melanoma NSG mouse models.