Exploring the Potential of Momelotinib to Treat Diffuse Midline Glioma with ACVR1 Mutations
DOI:
https://doi.org/10.58445/rars.3516Keywords:
Diffuse Midline Glioma, Pediatric Brain Tumor, Cancer, Momelotinib, Drug Repurposing, ACVR1, JAKAbstract
Diffuse Midline Glioma, or DMG, is an incurable high-grade pediatric brain tumor with a prognosis of less than one year. While the most defining mutation is H3K27M, mutations within the ACVR1, JAK1, and JAK2 genes are also associated with DMG. After years of extensive research, Jazz Pharmaceutical’s recent development of the ONC201 drug for those with a histone mutation marks a significant breakthrough by improving survival by approximately 10 months compared to the initial prognosis. However, there is still much room for improvement in advancing DMG treatment. Past research has noted overactivation of the BMP and JAK/STAT pathways as a common characteristic of DMG. As a result, inhibition of these pathways should be explored as a potential treatment method. Momelotinib, an ACVR1/JAK1/JAK2 inhibitor FDA-approved for the treatment of myelofibrosis, is a viable candidate. While previous research has examined other pathways to treat DMG, the use of momelotinib has not been previously examined in this context. PyRx, PyMol, and Biova Discovery Studio Visualizer were used to test the binding of momelotinib to relevant protein structures obtained from Protein Data Bank. Momelotinib was able to bind to both WT ACVR1, WT JAK1, and mutant ACVR1 with high binding affinities. This indicates momelotinib’s potential to bind to these proteins. However, further laboratory and clinical testing is necessary to truly confirm momelotinib’s potential to be used in treatment of DMG. While previous papers have confirmed momelotinib’s ability to bind to WT ACVR1, binding to mutant ACVR1 has not been previously explored.
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