Dual Inhibition of JAK2 and BET: The Therapeutic Potential of OHM-581 in Myelofibrosis and Hematologic Malignancies

OHM-581 is a novel small molecule that inhibits both JAK2 and BET proteins, offering a new therapeutic approach for myelofibrosis (MF) and other hematologic malignancies. Unlike the only approved JAK2 inhibitor, ruxolitinib, which provides limited benefits for most patients, OHM-581 has shown superior efficacy in preclinical models by reducing fibrosis, inducing apoptosis in post-MF secondary acute myeloid leukemia (sAML) blasts, and improving survival rates.

In vitro assays have demonstrated OHM-581's potent inhibitory effects on BRD4 and JAK2, with no significant hERG liability. The compound has exhibited significant anti-proliferative activity against several liquid cancer cell lines, including AML cell lines with MLL fusion or JAK2V617F mutations. OHM-581 effectively down-regulates cMYC expression and JAK2 signaling, and triggers apoptosis in MV4-11 cells.

The compound shows good solubility, metabolic stability, and oral bioavailability. It does not inhibit thiamine uptake, unlike fedratinib, another molecule in development for MF. In vivo studies using an MV4-11 xenograft model have shown robust tumor inhibition following OHM-581 treatment.

In conclusion, OHM-581's dual inhibition of JAK2 and BET holds promise as a therapeutic agent for MF and other hematologic malignancies. Current development activities are focused on further proof-of-concept analyses using preclinical models, with results expected to be reported.