DMG-41. Development of Brain-Penetrant ALK2 Inhibitors for Diffuse Intrinsic Pontine Glioma (DIPG): An Open Science Approach.
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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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".