Discovery of a potent and selective JAK1-targeting PROTAC degrader with anti-tumor activities.

[Display omitted] • This work first proved that momelotinib was a suitable warhead for the design of JAK1 PROTACs. • This work provides a new case study about JAK1 subtype-selective PROTACs. • Compound 10c may serve as a novel lead compound for antitumor drug discovery. • This work highlights the potential of JAK1-directed protein degradation as an antitumor therapeutic approach. Aberrant activation of the JAK-STAT pathway is evident in various human diseases including cancers. Proteolysis targeting chimeras (PROTACs) provide an attractive strategy for developing novel JAK-targeting drugs. Herein, a series of CRBN-directed JAK-targeting PROTACs were designed and synthesized utilizing a JAK1/JAK2 dual inhibitor—momelotinib as the warhead. The most promising compound 10c exhibited both good enzymatic potency and cellular antiproliferative effects. Western blot analysis revealed that compound 10c effectively and selectively degraded JAK1 in a proteasome-dependent manner (DC 50 = 214 nM). Moreover, PROTAC 10c significantly suppressed JAK1 and its key downstream signaling. Together, compound 10c may serve as a novel lead compound for antitumor drug discovery. [ABSTRACT FROM AUTHOR]