Targeting Activin Receptor-like Kinase 2 Using Heterobifunctional Protein Degraders.
Webb DT., Jones KL., Macabuag N., Bago R., Betts J., Bhattacharyya S., Clifton S., Tinson RAJ., Achara C., Gilbert S., Howell S., Drewry DH., Rogers R., Jones C., Ferguson KR., Bullock AN., Lindsay DM., Kerr WJ., Esmieu W.
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.