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  3. Targeting Activin Receptor-like Kinase 2 Using Heterobifunctional Protein Degraders

Targeting Activin Receptor-like Kinase 2 Using Heterobifunctional Protein Degraders

  • J Med Chem. 2026 May 14;69(9):11524-11546. doi: 10.1021/acs.jmedchem.6c00714.
Daniel T Webb 1 2,  Katherine L Jones 2,  Natsuko Macabuag 2,  Ruzica Bago 2,  Joshua Betts 2,  Sumit Bhattacharyya 2,  Steve Clifton 2,  Ryan A J Tinson 2,  Chigozie Achara 2,  Simon Gilbert 2,  Stefanie Howell 3,  David H Drewry 3,  Rebecca Rogers 4,  Chris Jones 4,  Kyle R Ferguson 5,  Alex N Bullock 5,  David M Lindsay 1,  William J Kerr 1,  William Esmieu 2
Affiliations

Affiliations

  • 1 Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow G1 1XL, United Kingdom.
  • 2 Discovery from Charles River, Charles River, Chesterford Research Park, Saffron Walden CB10 1XL, United Kingdom.
  • 3 Structural Genomics Consortium (SGC) and Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
  • 4 Division of Molecular Pathology and Division of Cancer Therapeutics, The Institute of Cancer Research, London SM2 5NG, United Kingdom.
  • 5 Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, United Kingdom.
PMID: 42076879 DOI: 10.1021/acs.jmedchem.6c00714
Abstract

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.

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