Targeting activin receptor-like kinase 2 using heterobifunctional protein degraders

Tools

Webb, Daniel T. and Jones, Katherine L. and Macabuag, Natsuko and Bago, Ruzica and Betts, Joshua and Bhattacharyya, Sumit and Clifton, Steve and Tinson, Ryan A. J. and Achara, Chigozie and Gilbert, Simon and Howell, Stefanie and Drewry, David H. and Rogers, Rebecca and Jones, Chris and Ferguson, Kyle R. and Bullock, Alex N. and Lindsay, David M. and Kerr, William J. and Esmieu, William (2026) Targeting activin receptor-like kinase 2 using heterobifunctional protein degraders. Journal of Medicinal Chemistry, 69 (9). pp. 11524-11546. ISSN 0022-2623 (https://doi.org/10.1021/acs.jmedchem.6c00714)

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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.

ORCID iDs

Webb, Daniel T., Jones, Katherine L., Macabuag, Natsuko, Bago, Ruzica, Betts, Joshua, Bhattacharyya, Sumit, Clifton, Steve, Tinson, Ryan A. J., Achara, Chigozie, Gilbert, Simon, Howell, Stefanie, Drewry, David H., Rogers, Rebecca, Jones, Chris, Ferguson, Kyle R., Bullock, Alex N., Lindsay, David M. ORCID logoORCID: https://orcid.org/0000-0003-4498-5094, Kerr, William J. ORCID logoORCID: https://orcid.org/0000-0002-1332-785X and Esmieu, William;
  • Item type:Article
    ID code:96185
    Dates:
    Date
    Event
    14 May 2026
    Published
    3 May 2026
    Published Online
    27 April 2026
    Accepted
    Subjects:Science > Chemistry
    Department:Faculty of Science > Pure and Applied Chemistry
    Depositing user: Pure Administrator
    Date deposited:07 May 2026 08:41
    Last modified:02 Jun 2026 07:12
    URI:https://strathprints.strath.ac.uk/id/eprint/96185
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