Targeting Activin Receptor-like Kinase 2 Using Heterobifunctional Protein Degraders

Journal article

Activin receptor-like kinase 2 (ACVR1/ALK2) regulates bone morphogenetic protein signaling, and ALK2 modulation has been identified as a promising therapeutic strategy for conditions including fibrodysplasia ossificans progressiva (FOP), diffuse intrinsic pontine glioma (DIPG), and glioblastoma. Herein, we report on the development of first-in-class ALK2 degraders, including M4K3233 (13), a potent and selective compound that was utilized as a chemical tool to study the mechanism of ALK2 degradation. Subsequent optimization of this compound resulted in M4K3250 (20), a compound with improved ALK2 degradation potency. The compounds described have utility for studying the role of ALK2 in human disease and possess translational potential in drug discovery.

Authors: Webb, DT; Jones, KL; Macabuag, N; Bago, R; Betts, J

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: American Chemical Society
• Journal: Journal of Medicinal Chemistry
• Volume: 69
• Issue: 9
• Pages: 11524-11546
• Publication date: 2026-05-04
• Acceptance date: 2026-04-27
• DOI: 10.1021/acs.jmedchem.6c00714
• EISSN: 1520-4804
• ISSN: 0022-2623
• Language: English
• Keywords: Kinase; Drug discovery; Protein kinase A; Drug; Degradation (telecommunications); Cell culture; Phosphorylation; Biological activity