DMG-41. Development of Brain-Penetrant ALK2 Inhibitors for Diffuse Intrinsic Pontine Glioma (DIPG): An Open Science Approach.

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.