WWQ-03-012 is a potent, specific and covalent inhibitor of JAK2‐V617F complex component DESI2 with IC50 of 47.3 nM, selectively degrades mutant JAK2.
deSUMOylases DESI2 is a novel component of the JAK2‐V617F complex, DESI2 is a critical mutation‐specific stabilizer of JAK2‐V617F.
WWQ-03-012 covalently targets Cys94 of DESI2, displays modest activity against UCHL1 (IC50 = 5956 nM) and USP30 (IC50 = 2028 nM) in a panel of purified DUBs, including UCHL1, USP30, JOSD1.
WWQ-03-012 promotes selective degradation of mutant JAK2‐V617F in HEL cells with DC50 of 543.6 nM (24 h), with minimal impact on WT JAK2 protein.
WWQ-03-012 induces JAK2 mutant leukemia cell death in preclinical models.
WWQ-03-012 (12.5 mg/kg, i.p. BID) significantly inhibits the tumor growth and myeloproliferative neoplasms (MPN) progression in JAK2V617F‐driven MPN in vivo, significantly reduces the JAK2‐V617F protein levels and downstream signal transduction in MPN mice.