In vivo efficacy of ALK2 inhibitors in a mouse model of fibrodysplasia ossificans progressiva
Authors/Creators
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1.
Ontario Institute for Cancer Research
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2.
University of Oxford
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3.
Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania
- 4. Agora Open Science Trust
Description
Diffuse Intrinsic Pontine Glioma (DIPG) is a rare and aggressive pediatric cancer located in the pons region of the brainstem, classified as a broader class of H3 K27M mutant Diffuse Midline Gliomas (DMG). Traditional drug development models struggle to address rare diseases like DIPG due to small patient populations and high risks.
M4K Pharma focuses on developing an ALK2 enzyme inhibitor, the first therapeutic designed specifically for DIPG. We are leveraging highly potent, selective, and drug-like molecules targeting this protein to create a promising therapeutic option for children affected by this devastating disease.
This entry includes data generated from in vivo mouse models of Fibrodysplasia Ossificans Progressiva (FOP) used to evaluate the pharmacological activity of the selective ALK2 inhibitors M4K2009, M4K2281, and M4K2308. The dataset contains detailed experimental records for each animal, including mouse identification number, sex, treatment group, dosing regimen (25, 50, or 100 mg/kg), and longitudinal body weight measurements collected across multiple study timepoints.
Additional data include dose calculations following treatment initiation and subsequent dosing periods, as well as experimental metadata such as blood collection timepoints, terminal perfusion status, and recombination efficiency measured from tail samples.
Phenotypic analyses demonstrated clear differences between compound-treated and vehicle-treated control groups. Animals treated with ALK2 inhibitors showed no grossly visible heterotopic ossification (HO), whereas control animals developed visible HO lesions with measurable ossification volumes, including evidence of contralateral limb involvement. These findings support the ability of pharmacological ALK2 inhibition to suppress pathological bone formation in the FOP model.
The dataset also includes pharmacokinetic analyses from treated animals, including plasma PK measurements and quantitative assessment of M4K2009, M4K2281, and M4K2308 concentrations in brain tissue.
Table of key terms and definitions of the project.
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Key term |
Definition |
|
Diffuse Intrinsic Pontine Glioma (DIPG) |
A rare, aggressive pediatric brain tumor located in the pons region of the brainstem (median survival 9-12 months). |
|
Diffuse midline glioma (DMG) |
Broader classification of aggressive midline brain tumors associated with H3K27M mutations. |
|
ACVR1 |
Gene encoding the ALK2 kinase; activating gain-of-function mutations present in ~25-30% of DIPG cases. |
|
ALK2 |
A BMP type I receptor serine/threonine kinase that drives aberrant signaling in ACVR1-mutant DIPG. |
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BMP signalling |
Bone morphogenetic protein pathway involved in cell differentiation and growth; dysregulated in ACVR1-mutant tumors. |
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H3K27M mutation |
A histone mutation commonly found in DMG/DIPG that alters epigenetic regulation and tumor biology. |
|
M4K2009 |
Lead small-molecule, ALK2 inhibitor selected for IND-enabling development. |
|
SMAD1/5 phosphorylation |
Downstream signaling event of ALK2 activation; reduced phosphorylation indicates target engagement. |
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Orthotopic mouse model |
In vivo tumor model where DIPG cells are implanted in the brainstem to mimic human disease. |
|
RCAS-ACVR1 model |
Genetically engineered mouse model expressing ACVR1 and H3K27M mutation to study DIPG. |
Notes
𝐀𝐛𝐨𝐮𝐭 𝐀𝐠𝐨𝐫𝐚 𝐎𝐩𝐞𝐧 𝐒𝐜𝐢𝐞𝐧𝐜𝐞 𝐓𝐫𝐮𝐬𝐭
Agora Open Science Trust is a Canadian charity whose mission is to accelerate the discovery and development of affordable new medicines through open science. Agora’s first initiative – M4K Pharma (‘Medicines for Kids’) – is using open science to drive preclinical and clinical development of a novel ALK2 inhibitor for the treatment of Diffuse Intrinsic Pontine Glioma (DIPG), a rare pediatric brain cancer. Agora’s pipeline of collaborative open science drug discovery programs has recently expanded to include programs for Spinal Bulbar Muscular Atrophy (SBMA), a rare genetic neuromuscular disorder, and Primary Sclerosing Cholangitis (PSC), a rare liver disease — both of which currently have no approved treatment.
Agora continues to welcome collaborative funding partners whose support will help advance M4K2009 into clinical evaluation and sustain its mission to develop affordable medicines through open science.
You can support its mission at https://www.agoraopensciencetrust.org/donate-to-our-mission
Notes
Funding acknowledgement:
We gratefully acknowledge the generous support of our funders and donors, whose contributions made this work possible, including Cancer Therapeutics Innovation Pipeline program at the Ontario Institute for Cancer Research (OICR) and the Krembil Foundation.
Notes
Note: Author names are presented alphabetically.
Files
M4K_ Mouse FOP Model_ Data.pdf
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