MTX-241F

Therapeutic resistance remains a major obstacle to successful clinical management of diffuse intrinsic pontine glioma (DIPG), a high-grade pediatric tumor of the brain stem. In nearly all patients, available therapies fail to prevent progression. Innovative combinatorial therapies that penetrate the blood–brain barrier and lead to long-term control of tumor growth are desperately needed. We identified mechanisms of resistance to radiotherapy, the standard of care for DIPG. On the basis of these findings, we rationally designed a brain-penetrant small molecule, MTX-241F, that is a highly selective inhibitor of EGFR and PI3 kinase family members, including the DNA repair protein DNA-PK. Preliminary studies demonstrated that micromolar levels of this inhibitor can be achieved in murine brain tissue and that MTX-241F exhibits promising single-agent efficacy and radiosensitizing activity in patient-derived DIPG neurospheres. Its physiochemical properties include high exposure in the brain, indicating excellent brain penetrance. Because radiotherapy results in double-strand breaks that are repaired by homologous recombination (HR) and non-homologous DNA end joining (NHEJ), we have tested the combination of MTX-241F with an inhibitor of Ataxia Telangiectasia Mutated to achieve blockade of HR and NHEJ, respectively, with or without radiotherapy. When HR blockers were combined with MTX-241F and radiotherapy, synthetic lethality was observed, providing impetus to explore this combination in clinically relevant models of DIPG.Our data provide proof-of-concept evidence to support advanced development of MTX-241F for the treatment of DIPG. Future studies will be designed to inform rapid clinical translation to ultimately impact patients diagnosed with this devastating disease.

The global resurgence of the monkeypox virus (MPXV) poses a serious threat to public health, necessitating the development of potent antiviral compounds. This study explored the potential of MPXV H1 phosphatase inhibitors using a computational biology approach, leveraging traditional knowledge from Indian Materia Medica. An in-house library of approximately 50,000 natural compounds from Indian Materia Medica was screened using molecular docking techniques, identifying 12,800 compounds with significant binding affinities, including ten hit compounds selected for further analysis. The top three hit compounds exhibited binding affinities as low as - 8.2 kcal/mol, surpassing the positive controls, Antimycin A (- 6.1 kcal/mol) and Tecovirimat (- 7.0 kcal/mol). These compounds were further optimized using Density Functional Theory (DFT), showing their significant electronic properties and redocked with the target. Molecular dynamics (MD) simulation demonstrated the structural stability of lead 3 and target complex over 200 ns with - 96.02 ± 1.00 kJ/mol binding energy, significantly outperforming the control Antimycin A (- 23.59 ± 2.97 kJ/mol) and Tecovirimat (- 49.07 ± 1.46 kJ/mol). These findings suggest that Lead 3 containing Lawsonia inermis, traditionally used for medicinal purposes, could be a potential source of antiviral agents against MPXV. This study provides a strong basis for further experimental validation and the development of novel therapeutic interventions against MPXV.