DMG-41. Development of Brain-Penetrant ALK2 Inhibitors for Diffuse Intrinsic Pontine Glioma (DIPG): An Open Science Approach.
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Bibliographic record
Abstract
Abstract Diffuse Intrinsic Pontine Glioma (DIPG) is a rare and aggressive pediatric cancer located in the pons region of the brainstem, classified as part of a broader class of H3 K27M mutant Diffuse Midline Gliomas (DMG). Focal radiation remains the standard of care; however the median survival is only 9-12 months, with no effective chemotherapeutic options available. Somatic missense mutations in the bone morphogenetic protein (BMP) type I receptor ACVR1 gene, which encodes activin receptor-like kinase-2 (ALK2), are present in approximately 25% of DMG tumours. Using an Open Science approach to promote transparency and collaboration, we previously reported ALK2 inhibitors with high potency (ALK2 IC50 < 10 nM, nanoBRET ALK2 IC50 < 20 nM), selectivity (>100-fold over ALK5) and brain penetration (Cbrain,4h/Cplasma,4h > 0.5, 10 mg/kg, NOD-SCID male mice). These inhibitors are highly orally bioavailable and demonstrate high in vivo exposure and dose linearity. In vitro, compounds have been screened in a panel of patient-derived DMG models including ACVR1 mutant and wild-type, with GI50s ranging from 0.3–14 µM, and selectivity for mutant over wild-type. In vivo, compounds showed an extension of survival in both an orthotopic PDX model (HSJD-DIPG-007, H3.3_K27M, ACVR1_R206H), and in an allograft of RCAS-ACVR1_R206H/H3.1_K27M in an immune competent background. From this series, we describe the selection process for a clinical development candidate. This work highlights the potential of ALK2 inhibitors as a therapeutic strategy for ACVR1 mutant gliomas and the value of Open Science in accelerating drug discovery for rare diseases.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.002 | 0.001 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it