Despite decades of research on new diffuse intrinsic pontine glioma (DIPG) treatments, little or no progress has been made on improving patient outcomes. 25% of DIPG tumours have gain of function mutations in the ACVR1 gene encoding the ALK2 receptor serine kinase. The development of brain penetrant ALK2 kinase inhibitors therefore offers potential for future DIPG treatments. In this work, we explored novel scaffold modifications of M4K2009, a 3,5-diphenylpyridine ALK2 kinase inhibitor previously reported by our group. We disclose the design, synthesis, and evaluation of a first-in-class set of 5- to 7-membered ether-linked and 7-membered amine-linked constrained inhibitors of ALK2. This rigidification strategy led us to the discovery of the amine-linked inhibitors M4K2304 and M4K2306, each with superior potency against ALK2. 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.
