Targeting activin receptor-like kinase 2 using heterobifunctional protein degraders

Daniel T. Webb; Katherine L. Jones; Natsuko Macabuag; Ruzica Bago; Joshua Betts; Sumit Bhattacharyya; Steve Clifton; Ryan A. J. Tinson; Chigozie Achara; Simon Gilbert; Stefanie Howell; David H. Drewry; Rebecca Rogers; Chris Jones; Kyle R. Ferguson; Alex N. Bullock; David M. Lindsay; William J. Kerr; William Esmieu

doi:10.1021/acs.jmedchem.6c00714

Targeting activin receptor-like kinase 2 using heterobifunctional protein degraders

Daniel T. Webb
, Katherine L. Jones
, Natsuko Macabuag
, Ruzica Bago
, Joshua Betts
, Sumit Bhattacharyya
, Steve Clifton
, Ryan A. J. Tinson
,  Chigozie Achara
, Simon Gilbert
, Stefanie Howell
, David H. Drewry
, Rebecca Rogers
, Chris Jones
, Kyle R. Ferguson
, Alex N. Bullock
, David M. Lindsay
, William J. Kerr^*
, William Esmieu

^*Corresponding author for this work

Pure And Applied Chemistry

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Pages (from-to)	11524-11546
Number of pages	23
Journal	Journal of Medicinal Chemistry
Volume	69
Issue number	9
Early online date	3 May 2026
DOIs	https://doi.org/10.1021/acs.jmedchem.6c00714
Publication status	Published - 14 May 2026

Funding

This work was supported by a Medical Research Scotland PhD studentship grant (PhD-50251-2020), with additional funding from Charles River Laboratories. K.R.F. was supported by an Oxford-The Simcox Family Graduate Scholarship and FOP Friends. A portion of this work (DHD and SH) was funded by The Cure Starts Now Foundation International, supporting the DIPG Collaborative. Supporting organizations of this funding include The Cure Starts Now Foundation, Brooke Healey Foundation, Melina Michelle Edenfield Foundation, The Cure Starts Now Australia, The Cure Starts Now Canada, Reflections Of Grace Foundation, Yuvaan Tiwari Foundation, Cure Brain Cancer Foundation, Aubreigh’s Army Foundation 328, Aidan's Avengers, Run DIPG, Musella Foundation, Love4Lucas Foundation, Whitley’s Wishes, Anna’s Bake Sale Foundation, The Ayla Foundation, The Isabella and Marcus Foundation, Love, Chloe Foundation, Lauren's Fight for Cure, Robert Connor Dawes Foundation, Ryan's Hope, The Gold Hope Project, Abby’s Corner Foundation, The DIPG/DMG Collaborative, Snapgrant.com. Our team is very grateful for this generous support.

Keywords

assays
degradation
inhibitors
mixtures
peptides and proteins

Access to Document

10.1021/acs.jmedchem.6c00714Licence: CC BY 4.0

Webb-etal-JMC-2026-Targeting-activin-receptor-like-kinase-2Final published version, 6.95 MBLicence: CC BY 4.0

Cite this

Webb, D. T., Jones, K. L., Macabuag, N., Bago, R., Betts, J., Bhattacharyya, S., Clifton, S., Tinson, R. A. J., Achara, C., Gilbert, S., Howell, S., Drewry, D. H., Rogers, R., Jones, C., Ferguson, K. R., Bullock, A. N., Lindsay, D. M., Kerr, W. J., & Esmieu, W. (2026). Targeting activin receptor-like kinase 2 using heterobifunctional protein degraders. Journal of Medicinal Chemistry, 69(9), 11524-11546. https://doi.org/10.1021/acs.jmedchem.6c00714

@article{b82285d6a4684e27a4f995cc1ca75727,

title = "Targeting activin receptor-like kinase 2 using heterobifunctional protein degraders",

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.",

keywords = "assays, degradation, inhibitors, mixtures, peptides and proteins",

author = "Webb, \{Daniel T.\} and Jones, \{Katherine L.\} and Natsuko Macabuag and Ruzica Bago and Joshua Betts and Sumit Bhattacharyya and Steve Clifton and Tinson, \{Ryan A. J.\} and  Chigozie Achara and Simon Gilbert and Stefanie Howell and Drewry, \{David H.\} and Rebecca Rogers and Chris Jones and Ferguson, \{Kyle R.\} and Bullock, \{Alex N.\} and Lindsay, \{David M.\} and Kerr, \{William J.\} and William Esmieu",

year = "2026",

month = may,

day = "14",

doi = "10.1021/acs.jmedchem.6c00714",

language = "English",

volume = "69",

pages = " 11524--11546",

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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 2026, 'Targeting activin receptor-like kinase 2 using heterobifunctional protein degraders', Journal of Medicinal Chemistry, vol. 69, no. 9, pp. 11524-11546. https://doi.org/10.1021/acs.jmedchem.6c00714

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T1 - Targeting activin receptor-like kinase 2 using heterobifunctional protein degraders

AU - Webb, Daniel T.

AU - Jones, Katherine L.

AU - Macabuag, Natsuko

AU - Bago, Ruzica

AU - Betts, Joshua

AU - Bhattacharyya, Sumit

AU - Clifton, Steve

AU - Tinson, Ryan A. J.

AU - Achara,  Chigozie

AU - Gilbert, Simon

AU - Howell, Stefanie

AU - Drewry, David H.

AU - Rogers, Rebecca

AU - Jones, Chris

AU - Ferguson, Kyle R.

AU - Bullock, Alex N.

AU - Lindsay, David M.

AU - Kerr, William J.

AU - Esmieu, William

PY - 2026/5/14

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AB - 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.

KW - assays

KW - degradation

KW - inhibitors

KW - mixtures

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DO - 10.1021/acs.jmedchem.6c00714

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JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

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ER -

Targeting activin receptor-like kinase 2 using heterobifunctional protein degraders

Abstract

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Keywords

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