Abstract 3067: OHM-581, a dual JAK2-BET inhibitor for the treatment of myelofibrosis and other hematologic malignancies
Authors: Upadhayaya Ram S. , Kethiri Raghava Reddy , Morris Stephan W. , Shepard H. Michael , Saks Samuel R. , Weickert Michael J. 
Published: August 2019

Abstract
Ruxolitinib is the only JAK2 inhibitor approved for myelofibrosis (MF). Although JAK2 inhibitor therapy improves splenomegaly and systemic symptoms, it does not significantly reduce the MF clone or alter the natural history and survival in most patients. The novel small molecule OHM-581 not only inhibits JAK2, but also BET (bromodomain and extra terminal) proteins such as BRD4. Dual JAK2 and BET inhibition using other molecules has shown superior efficacy in murine MF models compared with JAK2 inhibition alone including amelioration of fibrosis, synergistic induction of apoptosis of primary patient, post-MF secondary acute myeloid leukemia (sAML) blasts, and significant improvement of the survival of mice engrafted with human sAML cells. OHM-581 is being developed for the treatment of MF and other hematologic malignancies to leverage these advantages of dual JAK2-BET inhibition.
Results: In vitro biochemical assays show OHM-581 to inhibit BRD4 BD1 and BD2 with IC50s of 189 and 116 nM, respectively, and JAK2 with an IC50 of 7.1 nM (JAK1=244 nM; JAK3=76 nM). No significant hERG liability was seen. OHM-581 displays significant anti-proliferative activity against multiple liquid cancer cell lines. Notably, the GI50 values for MV4-11 (AML, MLL fusion+), HEL 92.1.7 (AML, JAK2V617F+) and UKE-1 (AML, JAK2V617F+) are 32, 87 and 140 nM, respectively. Consistent with its mechanism of action, OHM-581 robustly down-regulates cMYC expression (cMYC mRNA down-regulation IC50=18.6 nM compared with 41.4 nM for BET inhibitor JQ1) and JAK2 signaling. Moreover, the compound triggers apoptosis in MV4-11 cells (~7-fold increase in Caspase 3/7 activity at 24-h). OHM-581 does not reflect an efflux liability, the efflux ratio being nearly 1.8. OHM-581 is soluble in PBS pH7.4 at 26 µM and metabolically stable with nearly 51%, 67% and 88% remaining in mouse, rat and human liver microsomes, respectively, after 30 min. OHM-581 exhibits an oral bioavailability of ~40%. As compared to the small molecule fedratinib, which is also being developed for MF, OHM-581 does not inhibit thiamine uptake. Dose proportionality with a greater than proportional increase in both Cmax and AUC at doses up to 60 mg/kg, and a saturation of Cmax at doses of 60 mg/kg and higher, are observed for OHM-581. In vivo efficacy studies using an MV4-11 xenograft model demonstrate robust tumor inhibition (~75-90%) following doses of 30 and 60 mg/kg po BID for 20 days.
Conclusion: OHM-581 is a novel dual inhibitor of JAK2 and BET that has potential as a therapeutic agent for MF and other hematologic malignancies. In addition to IND-enabling studies, current OHM-581 development activities are focused on further proof-of-concept analyses using preclinical models of MF and other myeloproliferative neoplasms, with results to be reported.
Citation Format: Ram S. Upadhayaya, Raghava Reddy Kethiri, Stephan W. Morris, H. Michael Shepard, Samuel R. Saks, Michael J. Weickert. OHM-581, a dual JAK2-BET inhibitor for the treatment of myelofibrosis and other hematologic malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3067.