From 800 Compounds to One Candidate: A Major Milestone in the Fight Against DIPG

In recognition of Rare Disease Day, we are sharing the story behind our recent milestone: the selection of M4K2009 as a lead development candidate for DIPG.

Diffuse Intrinsic Pontine Glioma (DIPG), classified as part of a broader class of H3K27M mutant Diffuse Midline Gliomas (DMG), remains one of the most devastating childhood brain cancers. Striking at a young age and progressing rapidly, it offers families few treatment options and virtually no cure. Despite years of investigation, scientists still do not fully understand its pathogenesis, which makes the disease particularly difficult to treat. 

One of the most promising avenues of research has been the discovery that a subset of DIPG tumors carries mutations in the ACVR1 gene, which encodes the ALK2 protein. While these mutations alone do not explain the full pathogenesis of the disease, the development of compounds that inhibit ALK2 has emerged as a potentially transformative treatment strategy for patients.

The Discovery of M4K2009

Given the relatively small population of patients with this disease, there is little financial incentive for typical biotech and pharma companies to invest in a dedicated drug discovery program for DIPG. That inspired the mission of M4K Pharma, a virtual biotech company focused on developing affordable therapies for underserved pediatric conditions.

Within M4K Pharma’s open science drug discovery program, researchers from the Ontario Institute for Cancer Research (OICR), Institute of Cancer Research (ICR) and collaborators around the world have worked to design, test, and refine nearly 800 new compounds that target ALK2. Out of this work, the team identified compounds that met the essential criteria for an effective medicine: they were highly potent, showed strong selectivity to avoid unwanted side effects, successfully entered the brain, and could be given in a way that ensured the right levels reached the tumor. This effort formed the foundation of a rigorous lead optimization campaign, through which a number of the most promising compounds were evaluated head-to-head.

After extensive evaluation, M4K2009 was unanimously selected by an expert committee as the lead development candidate. It combines potency and selectivity against ALK2 with the ability to reach brain tumors effectively, while also showing excellent safety and stability in early testing. In preclinical models that closely mimic DIPG in patients, M4K2009 not only engaged its target but also extended survival, providing powerful evidence of its potential. Just as importantly, M4K2009 offered a practical advantage: it can be manufactured more efficiently and cost-effectively than the other candidates, requiring fewer synthetic steps from readily available starting materials. 

Open Science in Action

What makes this milestone even more remarkable is how it was accomplished. M4K Pharma operates under an open science model, meaning that data are shared broadly and in real time with the research community. This transparency avoids duplication of effort and accelerates discovery. In this case, cross-functional research teams were able to work hand in hand across institutions, compressing timelines that traditionally take years. Patient-derived DIPG cell lines were tested openly, as were advanced in vivo mouse models that mimic the biology of the disease. Every finding was part of a collective effort to bring new therapies closer to children in need.

A Milestone and a Call to Action

The nomination of M4K2009 as a lead development candidate is a milestone for M4K Pharma that signals real hope for families affected by DIPG. It represents years of collective work, the dedication of scientists across academia and industry, and the unwavering commitment of funders and foundations who make this research possible. It also demonstrates the power of open science, where progress is not confined to the walls of a single organization but shared to benefit the entire community.

With M4K2009 now moving into IND-enabling studies, the program enters an exciting new phase that brings us closer to clinical trials. Achievements like this are only possible because of the collaborative network of researchers, families, and supporters who believe that children with rare diseases deserve better. We are deeply grateful to our collaborators, OICR, ICR, Charles River Laboratories, the Structural Genomics Consortium, University of Pennsylvania, Montreal Children’s Hospital/McGill University, Children’s Cancer Institute, Sant Joan de Deu Hospital, Reaction Biology and GL Chemtec for their continued partnership. We received funding from the Cancer Therapeutics Innovation Pipeline (CTIP) and the Brain Tumour Charity for  lead optimization work that enabled the identification of this candidate compound, while the Krembil Foundation and Conscience Medicines Network have provided funding to support preclinical development. Their trust and investment laid the groundwork for this milestone.

As we work to advance M4K2009 towards clinical application, we invite partners to invest in the next phase of this journey. Continued funding from donors and foundations is critical to ensure that this promising compound reaches children with DIPG as quickly and affordably as possible. 

At M4K Pharma, we remain committed to developing medicines for rare childhood diseases through open science. With your support, we can turn this milestone into a lifesaving reality.