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Updated: Dec 12, 2025
A Protocol for Rapid Post-mortem Cell Culture of Diffuse Intrinsic Pontine Glioma DIPG
Published on: March 7, 2017
Leveraging an Open Science Drug Discovery Model to Develop CNS-Penetrant ALK2 Inhibitors for the Treatment of Diffuse
David Smil1, Jong Fu Wong2, Eleanor P Williams2
1Drug Discovery Program, Ontario Institute for Cancer Research, 661 University Avenue, MaRS Centre, West Tower, Toronto, Ontario M5G 0A3, Canada.
Abstract:
There are currently no effective chemotherapeutic drugs approved for the treatment of diffuse intrinsic pontine glioma (DIPG), an aggressive pediatric cancer resident in the pons region of the brainstem. Radiation therapy is beneficial but not curative, with the condition being uniformly fatal. Analysis of the genomic landscape surrounding DIPG has revealed that activin receptor-like kinase-2 (ALK2) constitutes a potential target for therapeutic intervention given its dysregulation in the disease. We adopted an open science approach to develop a series of potent, selective, orally bioavailable, and brain-penetrant ALK2 inhibitors based on the lead compound LDN-214117. Modest structural changes to the C-3, C-4, and C-5 position substituents of the core pyridine ring afforded compounds M4K2009, M4K2117, and M4K2163, each with a superior potency, selectivity, and/or blood-brain barrier (BBB) penetration profile. Robust in vivo pharmacokinetic (PK) properties and tolerability mark these inhibitors as advanced preclinical compounds suitable for further development and evaluation in orthotopic models of DIPG.
Insights
New ALK2 inhibitors show promise for treating diffuse intrinsic pontine glioma (DIPG), a fatal pediatric brain cancer. These orally available, brain-penetrant compounds offer a potential new therapeutic avenue for DIPG patients.
Area of Science:
- Oncology
- Pharmacology
- Neuroscience
Background:
- Diffuse intrinsic pontine glioma (DIPG) is an aggressive pediatric brainstem cancer with no effective chemotherapeutic treatments.
- Current treatments like radiation therapy offer limited efficacy, and the condition is uniformly fatal.
- Genomic analysis identifies dysregulated activin receptor-like kinase-2 (ALK2) as a potential therapeutic target in DIPG.
Purpose of the Study:
- To develop potent, selective, orally bioavailable, and brain-penetrant ALK2 inhibitors for DIPG treatment.
- To identify novel drug candidates based on the lead compound LDN-214117.
- To advance preclinical evaluation of ALK2 inhibitors in DIPG models.
Main Methods:
- Adopted an open science approach to medicinal chemistry.
- Synthesized and characterized novel ALK2 inhibitors with structural modifications to a pyridine core.
- Evaluated compound potency, selectivity, blood-brain barrier (BBB) penetration, and in vivo pharmacokinetic (PK) properties.
Main Results:
- Developed ALK2 inhibitors M4K2009, M4K2117, and M4K2163 with improved properties over the lead compound.
- Achieved superior potency, selectivity, and/or BBB penetration in the novel compounds.
- Demonstrated robust in vivo PK properties and tolerability, indicating suitability for further development.
Conclusions:
- Novel ALK2 inhibitors M4K2009, M4K2117, and M4K2163 are advanced preclinical candidates for DIPG.
- These compounds represent a promising therapeutic strategy for this currently untreatable pediatric cancer.
- Further evaluation in orthotopic DIPG models is warranted to assess therapeutic efficacy.
