WWQ-03-012

WWQ-03-012 is a selective DESI2 inhibitor with an IC₅₀ of 47.3 nM. WWQ-03-012 binds covalently to DESI2, blocks its enzymatic activity, and inhibits DESI2 -mediated deSUMOylation, deubiquitination and stabilization of mutant JAK2, thereby promoting the complete degradation of mutant JAK2 via the intracellular ubiquitin-proteasome system and inducing apoptosis, while exerting no significant effect on wild-type JAK2. WWQ-03-012 can be used for research on myeloproliferative neoplasms (MPN) and secondary acute myeloid leukemia (sAML), especially for hematological malignancies carrying the JAK2-V617F mutation and those resistant to Ruxolitinib ^[1].

In Vivo, WWQ-03-012 (12.5 mg/kg; i.p.; twice daily; up to 24 days) significantly reduces leukemia burden in JAK2V617F-driven acute myeloid leukemia xenografts, achieving an ≈ 4-fold reduction in bone marrow JAK2-V617F levels, with minimal observed toxicity^[1]. WWQ-03-012 (12.5 mg/kg; i.p.; twice daily; 15 days) significantly reduces JAK2V617F-driven MPN pathology in transgenic mice, including correcting peripheral blood abnormalities, reducing erythroid hyperplasia and splenomegaly, and suppressing leukemic stem cell populations, with minimal toxicity^[1].

In Vitro, WWQ-03-012 (with 6 h pre-incubation and 30 min substrate reaction) potently and selectively inhibits the enzymatic activity of recombinant DESI2, with an IC₅₀ value of 47.3 nM^[1]. WWQ-03-012 (100 μM) enhances the thermal stability of the target protein in recombinant experiments with purified DESI2 protein, causing a thermal shift of up to 3.5 °C^[1]. WWQ-03-012 (24-48 h) exhibits highly selective cytotoxicity in wild-type (WT) or JAK2-V617F-mutant MPN/AML cell lines, normal mouse CD34+ cells, bone marrow from healthy donors, and primary MPN samples (mutCALR or JAK2-V617F). It significantly and preferentially kills cells carrying the JAK2-V617F mutation, while exerting minimal effects on wild-type and CALR-mutant cells^[1]. WWQ-03-012 (0.1-10 μM; 24 h) exerts a selective degradation effect on mutant proteins in multiple JAK2-WT (K562) and JAK2-V617F mutant (HEL (DC₅₀ = 543.6 nM), DAMI, UKE-1, Ba/F3-JAK2-V617F) cell lines. It significantly induces JAK2-V617F degradation in a concentration-dependent manner, but has no obvious effect on the protein level of wild-type JAK2 (WT)^[1]. WWQ-03-012 (1 μM-10 μM; 24 h) promotes ubiquitination and SUMOylation of the mutant protein in HEL cells (JAK2-V617F), leading to a robust increase in polyubiquitin and SUMO2/3/4 signals on immunoprecipitated JAK2-V617F, accompanied by its protein degradation^[1]. WWQ-03-012 (10 μM; 24 h) also exhibits high targeting selectivity in mutant-driven MPN samples and UT7-MPLW515L cells, specifically degrading the JAK2-V617F protein without inducing degradation of JAK2 (WT) in mutCALR- or MPL-mutated samples^[1]. Combination treatment with WWQ-03-012 (24 h) and Ruxolitinib exerts synergistic cytotoxic effects on Ba/F3-JAK2-V617F cells and samples from drug-resistant patients, and significantly reduces the relative viability of cancer cells^[1].

References:
[1]. Mei H, et al. Targeting DESI2 as a Novel Therapeutic Strategy for JAK2-Mutant Leukemias. Advanced science (Weinheim, Baden-Wurttemberg, Germany). 2026 Feb;13(7):e15127.