Leveraging an Open Science Drug Discovery Model to Develop CNS-Penetrant ALK2 Inhibitors for the Treatment of Diffuse Intrinsic Pontine Glioma

There are currently no effective
chemotherapeutic drugs approved
for the treatment of diffuse intrinsic pontine glioma (DIPG), an aggressive
pediatric cancer resident in the pons region of the brainstem. Radiation
therapy is beneficial but not curative, with the condition being uniformly
fatal. Analysis of the genomic landscape surrounding DIPG has revealed
that activin receptor-like kinase-2 (ALK2) constitutes a potential
target for therapeutic intervention given its dysregulation in the
disease. We adopted an open science approach to develop a series of
potent, selective, orally bioavailable, and brain-penetrant ALK2 inhibitors
based on the lead compound LDN-214117. Modest structural
changes to the C-3, C-4, and C-5 position substituents of the core
pyridine ring afforded compounds M4K2009, M4K2117, and M4K2163, each with a superior potency, selectivity,
and/or blood–brain barrier (BBB) penetration profile. Robust in vivo pharmacokinetic (PK) properties and tolerability
mark these inhibitors as advanced preclinical compounds suitable for
further development and evaluation in orthotopic models of DIPG.