M4K2009 / M4K Pharma - LARVOL DELTA

Combination of ALK2 and cholesterol targeting agents exploits linked genetic and metabolic dependencies in diffuse midline glioma (SNO 2025) - "Drug-combination screens identified clinically well-tolerated statins, including simvastatin/lovastatin which target the rate-limiting cholesterol synthesis enzyme HMG-CoA reductase, and estrogen receptor inhibitors, including Tamoxifen, which exhibits off-target effects on EBP, as sensitisers to ALK2i...Forced differentiation of DMG cells to an astrocyte-like cell state increased cholesterol production and led to a significant decrease in M4K2009 sensitivity and synergy with statins, which was phenocopied when DMG cells were co-cultured with normal astrocytes. This was overcome in vitro, ex vivo and in vivo using a triple combination including a LXR agonist (LXR623) to promote cholesterol export. We identify a previously unappreciated link between ALK2 signalling and cholesterol homeostasis which may be exploited clinically by combining ALK2i with routinely-used statins and BBB-penetrant LXR agonists."

Brain Cancer • Diffuse Midline Glioma • Glioma • Solid Tumor • ABCA1 • ACVR1 • SREBF2

Combination of ALK2 and cholesterol targeting agents exploits linked genetic and metabolic dependencies in diffuse midline glioma (WFNOS 2025) - P1 | "Drug-combination screens identified clinically well-tolerated statins, including simvastatin/lovastatin which target the rate-limiting cholesterol synthesis enzyme HMG-CoA reductase, and estrogen receptor inhibitors, including Tamoxifen, which exhibits off-target effects on EBP, as sensitisers to ALK2i...Forced differentiation of DMG cells to an astrocyte-like cell state increased cholesterol production and led to a significant decrease in M4K2009 sensitivity and synergy with statins, which was phenocopied when DMG cells were co-cultured with normal astrocytes. This was overcome in vitro, ex vivo and in vivo using a triple combination including a LXR agonist (LXR623) to promote cholesterol export. We identify a previously unappreciated link between ALK2 signalling and cholesterol homeostasis which may be exploited clinically by combining ALK2i with routinely-used statins and BBB-penetrant LXR agonists."

Brain Cancer • Diffuse Midline Glioma • Glioma • Solid Tumor • ABCA1 • ACVR1 • SREBF2

Radiosynthesis and Preclinical PET Imaging of ALK2-Selective 3,5-Diphenylpyridine Inhibitors for a Rare Pediatric Brainstem Cancer (SNMMI 2025) - "Pharmacokinetic and pharmacodynamic properties were evaluated through PET imaging in male and female rodents at baseline, 30 min after pre-treatment with elacridar (5 mg/kg), or after combined elacridar pre-treatment with homologous blocking. Conclusion . A new series of radiolabeled 3,5-diphenylpyridines were synthesized and biologically evaluated to identify critical structural features that affect pontine tissue exposure. Significant improvements in brain permeability and radiometabolic stability were achieved compared to previous structures (e.g."

Preclinical • Brain Cancer • Diffuse Intrinsic Pontine Glioma • Glioma • Oncology • Pediatrics • Solid Tumor • ACVR1

Radiosynthesis and Preclinical PET Imaging of ALK2-Selective 3,5-Diphenylpyridine Inhibitors for a Rare Pediatric Brainstem Cancer (SNMMI 2025) - "Pharmacokinetic and pharmacodynamic properties were evaluated through PET imaging in male and female rodents at baseline, 30 min after pre-treatment with elacridar (5 mg/kg), or after combined elacridar pre-treatment with homologous blocking. Conclusion . A new series of radiolabeled 3,5-diphenylpyridines were synthesized and biologically evaluated to identify critical structural features that affect pontine tissue exposure. Significant improvements in brain permeability and radiometabolic stability were achieved compared to previous structures (e.g."

Preclinical • Brain Cancer • Diffuse Intrinsic Pontine Glioma • Glioma • Oncology • Pediatrics • Solid Tumor • ACVR1

Discovery of Conformationally Constrained ALK2 Inhibitors. (PubMed, J Med Chem) - "In this work, we explored novel scaffold modifications of M4K2009, a 3,5-diphenylpyridine ALK2 inhibitor previously reported by our group...Notably, M4K2304 and M4K2306 exhibit exceptional selectivity for ALK2 over ALK5, surpassing the reference compound. Preliminary studies on their in vivo pharmacokinetics, including blood-brain barrier penetration, revealed that these constrained scaffolds have favorable exposure and do open a novel chemical space for further optimization and future evaluation in orthotopic models of DIPG."

Journal • Brain Cancer • CNS Tumor • Diffuse Intrinsic Pontine Glioma • Glioma • Oncology • Solid Tumor • TGFBR1

Novel 18f labeled radiotracer for Neuroimaging activin receptor like kinase 2 (ACS-Sp 2024) - "M4K2009 and M4K2176 were synthesized as previously described...(B) Total and non-specific binding in rodent brain tissue (fresh-frozen, 10 um thick). Representative PET/CT summation images (0-120 min) in (C) Sprague-Dawley rat and (D) C57BL/6 mouse."

Brain Cancer • CNS Tumor • Diffuse Intrinsic Pontine Glioma • Glioma • Oncology • Pediatrics • Solid Tumor • ACVR1

Combined pharmacological and genetic screening to identify dependencies and combinations in ACVR1-mutant diffuse midline glioma (SNO 2022) - "Recently we reported that combinatorial treatment of ACVR1-mutant DIPG cells with vandetanib (RTK inhibitor) and everolimus (mTOR/ABC transporter inhibitor) was synergistic both in vitro and in vivo and was shown to be a feasible combination to trial clinically in this setting...Using a panel of 13 patient-derived ACVR1-mutant models (and 6 wild-type controls), we identified synergy between multiple chemotypes of ALK2i (M4K2009/LDN-214117) and PI3K/mTOR (AZD8055/everolimus) and MEK inhibitors (trametinib), reflecting the common co-segregation of PIK3CA/PIK3R1 alterations in these tumours...Additional hits include the serine/threonine kinase PKMYT1, a negative regulator of the G2/M checkpoint via a functionally redundant phosphorylation of CDK1/CCNB1 alongside WEE1; confirmatory drug assays with the WEE1 inhibitor AZD1775 resulted in a synergistic interaction with ALK2i in ACVR1-mutant cells...Preliminary pathway enrichment analysis (MAGeCKFlute) identified ALK2i-specific..."

Brain Cancer • Diffuse Midline Glioma • Glioma • Oncology • Solid Tumor • ACVR1 • CCNB1 • CDK1 • PIK3CA • PIK3R1 • PKMYT1