P1009: sklb054, a novel jak2 inhibitor, potently treats myeloproliferative neoplasm with jak2v617f mutation

Topic: 15. Myeloproliferative neoplasms - Biology & Translational Research Background:JAK2V617F mutation plays a driver pathogenic role in myeloproliferative neoplasms (MPNs), including primary myelofibrosis, polycythemia vera, and essential thrombocythemia. However, the approved JAK2 inhibitors, ruxolitinib and fedratinib, have been proved to cause hematologic toxicities and Wernick’s encephalopathy. Aims: This study aims to develop a novel JAK2 inhibitor, SKLB054, and investigate the effects of treating MPNs in vitro and in vivo. Methods:In vitro kinase assay was conducted to evaluate inhibition of JAK family by SKLB054 and molecular docking study was performed to explore whether SKLB054 bound to JAK2 protein. Proliferation, cell cycle, and apoptosis of JAK2V617F-dependent cells were examined to assess in vitro effect of SKLB054. Western blot was performed to explore the effect of SKLB054 on critical proteins in JAK/STAT and other signaling pathways. An erythroleukemia xenograft model and a JAK2V617F-induced MPN mouse model were established to evaluate the anti-tumor efficacy of SKLB054 in vivo. Results: SKLB054 was a novel JAK2 inhibitor, inhibiting JAK2 with an IC50 of 3 nM. It inhibited proliferation of various cell lines, induced G2/M cell cycle arrest, and promoted apoptosis of JAK2V617F-dependent cell lines. Moreover, SKLB054 suppressed phosphorylation of JAK2, STAT3, STAT5, and ERK in JAK-STAT pathway. In vivo, SKLB054 significantly inhibited tumor growth in an erythroleukemia xenograft model. Notably, in JAK2V617F-induced MPN murine model, SKLB054 markedly reduced hepatosplenomegaly and prolonged survival without obvious toxicity, which was better than ruxolitinib (Figure 1). In addition, SKLB054 also suppressed JAK-STAT signaling pathway in vivo.Figure 1. SKLB054 significantly attenuated splenomegaly of JAK2V617F-induced MPN mice. Summary/Conclusion: SKLB054, a potent JAK2 inhibitor, exhibited a promising therapeutic effect on MPNs. Keywords: Janus Kinase inhibitor, Myelofibrosis, Myeloproliferative disorder