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

3 June 2024
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.

How to Use Synapse Database to Search and Analyze Translational Medicine Data?

The transational medicine section of the Synapse database supports searches based on fields such as drug, target, and indication, covering the T0-T3 stages of translation. Additionally, it offers a historical conference search function as well as filtering options, view modes, translation services, and highlights summaries, providing you with a unique search experience.

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Taking obesity as an example, select "obesity" under the indication category and click search to enter the Translational Medicine results list page. By clicking on the title, you can directly navigate to the original page.

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By clicking the analysis button, you can observe that GLP-1R treatment for obesity has gained significant attention over the past three years, with preclinical research still ongoing in 2023. Additionally, there are emerging potential targets, such as GDF15, among others.

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Click on the image below to go directly to the Translational Medicine search interface.

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