Author(s) :

Adaya Dong, Yixiao Shen.

Volume/Issue :

Abstract :

Activin-A receptor type I (ALK2/ACVR1) is a central regulator of bone morphogenetic protein (BMP) signaling, essential for development and tissue homeostasis. The recurrent R206H mutation drives aberrant BMP pathway activation and underlies severe disorders including fibrodysplasia ossificans progressiva (FOP) and diffuse intrinsic pontine glioma (DIPG), with distinct clinical outcomes depending on cellular context. Current therapeutic strategies target mutant ALK2 through ligand-level blockade such as anti–Activin-A antibodies, and direct kinase inhibition using small molecules ranging from early dorsomorphin derivatives to next-generation candidates like BLU-782. Although these approaches have improved potency, significant challenges persist. Emerging structure-guided and allosteric strategies aimed at mutant-selective inhibition offer promising directions. Continued mechanistic and structural characterization of ALK2 mutants will be critical for developing safe, selective and effective therapies. This review aims to summarize recent advances in ALK2-targeted therapeutic strategies and to highlight key challenges and future directions in the development of selective and clinically effective ALK2 inhibitors.