PROTAC JAK1/2 degrader-1 is an orally active JAK1 / JAK2 PROTAC degrader, with DC50 values of 1.4 μM and 0.92 μM against JAK1 and JAK2, respectively. PROTAC JAK1/2 degrader-1 triggers degradation via a CRBN - and proteasome-dependent pathway. PROTAC JAK1/2 degrader-1 inhibits the secretion of tumor necrosis factor-α ( TNF-α ) and interleukin-6 ( IL-6 ). PROTAC JAK1/2 degrader-1 alleviates inflammatory responses and colon injury by inhibiting the JAK / STAT3 signaling pathway. PROTAC JAK1/2 degrader-1 can be used for the research of inflammatory bowel disease [1]. (Pink: JAK1 and JAK2 ligand; Blue: Cereblon ligand; Black: linker).
In Vivo, PROTAC JAK1/2 degrader-1 (compound A8) (10-40 mg/kg; p.o.; daily; 7 days) alleviates DSS-induced colitis in C57BL/6 mice via downregulation of the JAK/STAT3 signaling pathway[1].
In Vitro, PROTAC JAK1/2 degrader-1 (compound A8) (3 μM; 1 h followed by 6 h LPS stimulation) degrades JAK1 protein in LPS-stimulated Raw 264.7 cells[1]. PROTAC JAK1/2 degrader-1 (0.469-60 μM; 24 h) shows no cytotoxicity in Raw 264.7 cells[1]. PROTAC JAK1/2 degrader-1 (0.47-60 μM) induces dose-dependent degradation of JAK1 in LPS-stimulated Raw 264.7 cells with a DC50 of 1.40 μM[1]. PROTAC JAK1/2 degrader-1 (1.5 μM; 3 μM MG132 ) mediates JAK1 degradation in Raw 264.7 cells via a proteasome-dependent pathway, as degradation is inhibited by MG132, and the separate warhead and E3 ligase ligand components do not induce degradation[1]. PROTAC JAK1/2 degrader-1 (0.47-60 μM) is a selective JAK1/2 degrader, dose-dependently degrading JAK2 with a DC50 of 0.92 μM while not affecting JAK3 or TYK2 levels at concentrations up to 60 μM in Raw 264.7 cells[1]. PROTAC JAK1/2 degrader-1 (0.469-60 μM; 24 h) suppresses NO production in LPS-stimulated Raw 264.7 cells in a dose-dependent manner, with significant inhibition starting at 0.469 μM[1]. PROTAC JAK1/2 degrader-1 (0.05-60 μM; 24 h) suppresses IL-6 and TNF-α secretion in LPS-stimulated Raw 264.7 cells with IC50 values of 12.89 μM and 17.17 μM, respectively[1].
References:
[1]. Li G, et al. Development of potent JAK1/2 PROTAC degraders for the treatment of inflammatory bowel diseases. European journal of medicinal chemistry. 2026 Jan 15;302(Pt 3):118374.
In Vivo, PROTAC JAK1/2 degrader-1 (compound A8) (10-40 mg/kg; p.o.; daily; 7 days) alleviates DSS-induced colitis in C57BL/6 mice via downregulation of the JAK/STAT3 signaling pathway[1].
In Vitro, PROTAC JAK1/2 degrader-1 (compound A8) (3 μM; 1 h followed by 6 h LPS stimulation) degrades JAK1 protein in LPS-stimulated Raw 264.7 cells[1]. PROTAC JAK1/2 degrader-1 (0.469-60 μM; 24 h) shows no cytotoxicity in Raw 264.7 cells[1]. PROTAC JAK1/2 degrader-1 (0.47-60 μM) induces dose-dependent degradation of JAK1 in LPS-stimulated Raw 264.7 cells with a DC50 of 1.40 μM[1]. PROTAC JAK1/2 degrader-1 (1.5 μM; 3 μM MG132 ) mediates JAK1 degradation in Raw 264.7 cells via a proteasome-dependent pathway, as degradation is inhibited by MG132, and the separate warhead and E3 ligase ligand components do not induce degradation[1]. PROTAC JAK1/2 degrader-1 (0.47-60 μM) is a selective JAK1/2 degrader, dose-dependently degrading JAK2 with a DC50 of 0.92 μM while not affecting JAK3 or TYK2 levels at concentrations up to 60 μM in Raw 264.7 cells[1]. PROTAC JAK1/2 degrader-1 (0.469-60 μM; 24 h) suppresses NO production in LPS-stimulated Raw 264.7 cells in a dose-dependent manner, with significant inhibition starting at 0.469 μM[1]. PROTAC JAK1/2 degrader-1 (0.05-60 μM; 24 h) suppresses IL-6 and TNF-α secretion in LPS-stimulated Raw 264.7 cells with IC50 values of 12.89 μM and 17.17 μM, respectively[1].
References:
[1]. Li G, et al. Development of potent JAK1/2 PROTAC degraders for the treatment of inflammatory bowel diseases. European journal of medicinal chemistry. 2026 Jan 15;302(Pt 3):118374.