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Updated: Dec 22, 2025
A Protocol for Rapid Post-mortem Cell Culture of Diffuse Intrinsic Pontine Glioma DIPG
Published on: March 7, 2017
Targeting ALK2: An Open Science Approach to Developing Therapeutics for the Treatment of Diffuse Intrinsic Pontine
Deeba Ensan1,2, David Smil2, Carlos A Zepeda-Velázquez2
1Department of Pharmacology and Toxicology, University of Toronto, Medical Sciences Building, Room 4207, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada.
Abstract:
Diffuse intrinsic pontine glioma is an aggressive pediatric cancer for which no effective chemotherapeutic drugs exist. Analysis of the genomic landscape of this disease has led to the identification of the serine/threonine kinase ALK2 as a potential target for therapeutic intervention. In this work, we adopted an open science approach to develop a series of potent type I inhibitors of ALK2 which are orally bio-available and brain-penetrant. Initial efforts resulted in the discovery of M4K2009, an analogue of the previously reported ALK2 inhibitor LDN-214117. Although highly selective for ALK2 over the TGF-βR1 receptor ALK5, M4K2009 is also moderately active against the hERG potassium channel. Varying the substituents of the trimethoxyphenyl moiety gave rise to an equipotent benzamide analogue M4K2149 with reduced off-target affinity for the ion channel. Additional modifications yielded 2-fluoro-6-methoxybenzamide derivatives (26a-c), which possess high inhibitory activity against ALK2, excellent selectivity, and superior pharmacokinetic profiles.
Insights
Researchers developed new ALK2 inhibitors for diffuse intrinsic pontine glioma. These orally available, brain-penetrant drugs show high selectivity and improved safety profiles for treating this pediatric cancer.
Area of Science:
- Oncology
- Medicinal Chemistry
- Pharmacology
Background:
- Diffuse intrinsic pontine glioma (DIPG) is a fatal pediatric brain cancer with no effective chemotherapy.
- Genomic analysis identified the serine/threonine kinase ALK2 as a potential therapeutic target for DIPG.
Purpose of the Study:
- To develop potent, orally bio-available, and brain-penetrant type I ALK2 inhibitors using an open science approach.
- To identify novel drug candidates with improved selectivity and pharmacokinetic properties for DIPG treatment.
Main Methods:
- Structure-based drug design and medicinal chemistry optimization.
- In vitro biochemical and cellular assays to assess ALK2 inhibition and selectivity.
- Pharmacokinetic studies to evaluate oral bioavailability and brain penetration.
Main Results:
- Discovery of M4K2009, a selective ALK2 inhibitor, with moderate hERG channel activity.
- Development of M4K2149, a benzamide analogue with equipotent ALK2 inhibition and reduced hERG activity.
- Identification of 2-fluoro-6-methoxybenzamide derivatives (26a-c) with high ALK2 potency, excellent selectivity, and superior pharmacokinetic profiles.
Conclusions:
- Novel ALK2 inhibitors have been successfully developed through an open science approach.
- The identified compounds demonstrate potential as effective therapeutics for diffuse intrinsic pontine glioma.
- Further investigation of these compounds is warranted for clinical development against DIPG.
