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A small molecule targeting ALK1 prevents Notch cooperativity and inhibits functional angiogenesis.

Kerr G, Sheldon H, Chaikuad A, Alfano I, von Delft F, Bullock AN, Harris AL
Angiogenesis 18 209-17 (2015)
Cited: 45 times
EuropePMC logo PMID: 25557927

Abstract

Activin receptor-like kinase 1 (ALK1, encoded by the gene ACVRL1) is a type I BMP/TGF-β receptor that mediates signalling in endothelial cells via phosphorylation of SMAD1/5/8. During angiogenesis, sprouting endothelial cells specialise into tip cells and stalk cells. ALK1 synergises with Notch in stalk cells to induce expression of the Notch targets HEY1 and HEY2 and thereby represses tip cell formation and angiogenic sprouting. The ALK1-Fc soluble protein fusion has entered clinic trials as a therapeutic strategy to sequester the high-affinity extracellular ligand BMP9. Here, we determined the crystal structure of the ALK1 intracellular kinase domain and explored the effects of a small molecule kinase inhibitor K02288 on angiogenesis. K02288 inhibited BMP9-induced phosphorylation of SMAD1/5/8 in human umbilical vein endothelial cells to reduce both the SMAD and the Notch-dependent transcriptional responses. In endothelial sprouting assays, K02288 treatment induced a hypersprouting phenotype reminiscent of Notch inhibition. Furthermore, K02288 caused dysfunctional vessel formation in a chick chorioallantoic membrane assay of angiogenesis. Such activity may be advantageous for small molecule inhibitors currently in preclinical development for specific BMP gain of function conditions, including diffuse intrinsic pontine glioma and fibrodysplasia ossificans progressiva, as well as more generally for other applications in tumour biology.

Reviews - 3my0 mentioned but not cited (1)

  1. Recent Advances in ALK2 Inhibitors. Rooney L, Jones C. ACS Omega 6 20729-20734 (2021)

Articles - 3my0 mentioned but not cited (11)

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Reviews citing this publication (14)

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Articles citing this publication (19)

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  3. DLL4/Notch1 and BMP9 Interdependent Signaling Induces Human Endothelial Cell Quiescence via P27KIP1 and Thrombospondin-1. Rostama B, Turner JE, Seavey GT, Norton CR, Gridley T, Vary CP, Liaw L. Arterioscler Thromb Vasc Biol 35 2626-2637 (2015)
  4. Comparison of newly developed anti-bone morphogenetic protein 4 llama-derived antibodies with commercially available BMP4 inhibitors. Calpe S, Correia AC, Sancho-Serra Mdel C, Krishnadath KK. MAbs 8 678-688 (2016)
  5. Development of Macrocycle Kinase Inhibitors for ALK2 Using Fibrodysplasia Ossificans Progressiva-Derived Endothelial Cells. Sánchez-Duffhues G, Williams E, Benderitter P, Orlova V, van Wijhe M, Garcia de Vinuesa A, Kerr G, Caradec J, Lodder K, de Boer HC, Goumans MJ, Eekhoff EMW, Morales-Piga A, Bachiller-Corral J, Koolwijk P, Bullock AN, Hoflack J, Ten Dijke P. JBMR Plus 3 e10230 (2019)
  6. Opposing Effects of Growth and Differentiation Factors in Cell-Fate Specification. Chang KC, Sun C, Cameron EG, Madaan A, Wu S, Xia X, Zhang X, Tenerelli K, Nahmou M, Knasel CM, Russano KR, Hertz J, Goldberg JL. Curr Biol 29 1963-1975.e5 (2019)
  7. Identification of RSK and TTK as Modulators of Blood Vessel Morphogenesis Using an Embryonic Stem Cell-Based Vascular Differentiation Assay. Hammoud L, Adams JR, Loch AJ, Marcellus RC, Uehling DE, Aman A, Fladd C, McKee TD, Jo CEB, Al-Awar R, Egan SE, Rossant J. Stem Cell Reports 7 787-801 (2016)
  8. Compound genetically engineered mouse models of cancer reveal dual targeting of ALK1 and endoglin as a synergistic opportunity to impinge on angiogenic TGF-β signaling. Eleftheriou NM, Sjölund J, Bocci M, Cortez E, Lee SJ, Cunha SI, Pietras K. Oncotarget 7 84314-84325 (2016)
  9. Discovery of 3-(4-sulfamoylnaphthyl)pyrazolo[1,5-a]pyrimidines as potent and selective ALK2 inhibitors. Jiang JK, Huang X, Shamim K, Patel PR, Lee A, Wang AQ, Nguyen K, Tawa G, Cuny GD, Yu PB, Zheng W, Xu X, Sanderson P, Huang W. Bioorg Med Chem Lett 28 3356-3362 (2018)
  10. Comment Towards a cure for Fibrodysplasia ossificans progressiva. Sanchez-Duffhues G, de Gorter DJ, Ten Dijke P. Ann Transl Med 4 S28 (2016)
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  13. Differential BMP Signaling Mediates the Interplay Between Genetics and Leaflet Numbers in Aortic Valve Calcification. Jung JJ, Ahmad AA, Rajendran S, Wei L, Zhang J, Toczek J, Nie L, Kukreja G, Salarian M, Gona K, Ghim M, Chakraborty R, Martin KA, Tellides G, Heistad D, Sadeghi MM. JACC Basic Transl Sci 7 333-345 (2022)
  14. Comprehensive analysis of pyroptosis-related gene signatures for glioblastoma immune microenvironment and target therapy. Wang Z, Dai Z, Zhang H, Zhang N, Liang X, Peng L, Zhang J, Liu Z, Peng Y, Cheng Q, Liu Z. Cell Prolif 56 e13376 (2023)
  15. Identification of liver-derived bone morphogenetic protein (BMP)-9 as a potential new candidate for treatment of colorectal cancer. Cai C, Itzel T, Gaitantzi H, de la Torre C, Birgin E, Betge J, Gretz N, Teufel A, Rahbari NN, Ebert MP, Breitkopf-Heinlein K. J Cell Mol Med 26 343-353 (2022)
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  17. Computational and Experimental Analyses for Pathogenicity Prediction of ACVRL1 Missense Variants in Hereditary Hemorrhagic Telangiectasia. Iwasa T, Urasaki A, Kakihana Y, Nagata-Akaho N, Harada Y, Takeda S, Kawamura T, Shiraishi I, Kurosaki K, Morisaki H, Yamada O, Nakagawa O. J Clin Med 12 5002 (2023)
  18. Endothelial tip/stalk cell selection requires BMP9-induced βIV-spectrin expression during sprouting angiogenesis. Ahmed T, Ramonett A, Kwak EA, Kumar S, Flores PC, Ortiz HR, Langlais PR, Hund TJ, Mythreye K, Lee NY. Mol Biol Cell 34 ar72 (2023)
  19. Prioritization and functional validation of target genes from single-cell transcriptomics studies. Sokol L, Cuypers A, Truong AK, Bouché A, Brepoels K, Souffreau J, Rohlenova K, Vinckier S, Schoonjans L, Eelen G, Dewerchin M, de Rooij LPMH, Carmeliet P. Commun Biol 6 648 (2023)


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