Abstract A022: Discovery of conformationally constrained ALK2 inhibitors for the treatment of Diffuse Intrinsic Pontine Glioma (DIPG)
Bibliographic record
Abstract
Abstract Despite considerable research on new therapeutics to treat DIPG, a universally fatal grade IV pediatric CNS tumor located in the pons region of the brainstem, there has been minimal progress. Somatic missense mutations in the bone morphogenetic protein (BMP) type I receptor ACVR1 gene encoding activin receptor-like kinase-2 (ALK2) are present in approximately 33% of children with DIPG, prompting our initial efforts towards the development of M4K2009, a 3,5-diphenylpyridine ALK2 inhibitor. Looking to improve potency, selectivity, and brain penetration, we subsequently designed, synthesized, and evaluated a first-in-class set of 5- to 7-member ether-linked and 7-member amine-linked conformationally constrained ALK2 inhibitors including M4K2308, M4K2281, M4K2304 and M4K2306. Overall, these new compounds are highly potent (ALK2 IC50 < 10 nM, nanoBRET ALK2 IC50 < 20 nM), selective (>100-fold over ALK5), brain-penetrant (Cbrain,4h/Cplasma,4h > 3, 10 mg/kg, NOD-SCID male mice) and show in vivo exposure (Cplasma,6h = 1−2 µM, 25 mg/kg, NOD-SCID male mice). In particular, M4K2308 displayed a good balance of potency and DMPK properties and is currently undergoing preclinical evaluation by M4K Pharma. Citation Format: David Smil, Héctor González-Álvarez, Deeba Ensan, Jong Fu Wong, Julien Cros, Laurent Hoffer, Taira Kiyota, Brian J. Wilson, Carlos A. Zepeda-Velázquez, Ahmed Aman, Methvin B. Isaac, Tao Xin, Alex N. Bullock, Peter B. Sampson, Rima Al-awar. Discovery of conformationally constrained ALK2 inhibitors for the treatment of Diffuse Intrinsic Pontine Glioma (DIPG) [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr A022.
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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 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 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".