Targeting ALK2: An Open Science Approach to Developing Therapeutics for the Treatment of Diffuse Intrinsic Pontine Glioma

Diffuse
intrinsic pontine glioma is an aggressive pediatric cancer
for which no effective chemotherapeutic drugs exist. Analysis of the
genomic landscape of this disease has led to the identification of
the serine/threonine kinase ALK2 as a potential target for therapeutic
intervention. In this work, we adopted an open science approach to
develop a series of potent type I inhibitors of ALK2 which are orally
bio-available and brain-penetrant. Initial efforts resulted in the
discovery of M4K2009, an analogue of the previously reported
ALK2 inhibitor LDN-214117. Although highly selective
for ALK2 over the TGF-βR1 receptor ALK5, M4K2009 is also moderately active against the hERG potassium channel. Varying
the substituents of the trimethoxyphenyl moiety gave rise to an equipotent
benzamide analogue M4K2149 with reduced off-target affinity
for the ion channel. Additional modifications yielded 2-fluoro-6-methoxybenzamide
derivatives (26a–c), which possess high inhibitory
activity against ALK2, excellent selectivity, and superior pharmacokinetic
profiles.