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Structural basis for specificity of TGFβ family receptor small molecule inhibitors.

Ogunjimi AA, Zeqiraj E, Ceccarelli DF, Sicheri F, Wrana JL, David L
Cell Signal 24 476-483 (2012)
Cited: 42 times
EuropePMC logo PMID: 21983015

Abstract

Transforming growth factor-β (TGFβ) receptor kinase inhibitors have a great therapeutic potential. SB431542 is one of the mainly used kinase inhibitors of the TGFβ/Activin pathway receptors, but needs improvement of its EC(50) (EC(50)=1 μM) to be translated to clinical use. A key feature of SB431542 is that it specifically targets receptors from the TGFβ/Activin pathway but not the closely related receptors from the bone morphogenic proteins (BMP) pathway. To understand the mechanisms of this selectivity, we solved the crystal structure of the TGFβ type I receptor (TβRI) kinase domain in complex with SB431542. We mutated TβRI residues coordinating SB431542 to their counterparts in activin-receptor like kinase 2 (ALK2), a BMP receptor kinase, and tested the kinase activity of mutated TβRI. We discovered that a Ser280Thr mutation yielded a TβRI variant that was resistant to SB431542 inhibition. Furthermore, the corresponding Thr283Ser mutation in ALK2 yielded a BMP receptor sensitive to SB431542. This demonstrated that Ser280 is the key determinant of selectivity for SB431542. This work provides a framework for optimising the SB431542 scaffold to more potent and selective inhibitors of the TGFβ/Activin pathway.

Articles - 3tzm mentioned but not cited (23)

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Reviews citing this publication (1)

  1. Structural biology of the TGFβ family. Goebel EJ, Hart KN, McCoy JC, Thompson TB. Exp Biol Med (Maywood) 244 1530-1546 (2019)

Articles citing this publication (18)

  1. Switch enhancers interpret TGF-β and Hippo signaling to control cell fate in human embryonic stem cells. Beyer TA, Weiss A, Khomchuk Y, Huang K, Ogunjimi AA, Varelas X, Wrana JL. Cell Rep 5 1611-1624 (2013)
  2. Preclinical assessment of galunisertib (LY2157299 monohydrate), a first-in-class transforming growth factor-β receptor type I inhibitor. Yingling JM, McMillen WT, Yan L, Huang H, Sawyer JS, Graff J, Clawson DK, Britt KS, Anderson BD, Beight DW, Desaiah D, Lahn MM, Benhadji KA, Lallena MJ, Holmgaard RB, Xu X, Zhang F, Manro JR, Iversen PW, Iyer CV, Brekken RA, Kalos MD, Driscoll KE. Oncotarget 9 6659-6677 (2018)
  3. ERK1/2 directly acts on CTGF/CCN2 expression to mediate myocardial fibrosis in cardiomyopathy caused by mutations in the lamin A/C gene. Chatzifrangkeskou M, Le Dour C, Wu W, Morrow JP, Joseph LC, Beuvin M, Sera F, Homma S, Vignier N, Mougenot N, Bonne G, Lipson KE, Worman HJ, Muchir A. Hum Mol Genet 25 2220-2233 (2016)
  4. Structural basis for potency differences between GDF8 and GDF11. Walker RG, Czepnik M, Goebel EJ, McCoy JC, Vujic A, Cho M, Oh J, Aykul S, Walton KL, Schang G, Bernard DJ, Hinck AP, Harrison CA, Martinez-Hackert E, Wagers AJ, Lee RT, Thompson TB. BMC Biol 15 19 (2017)
  5. Characterization of TGFβ signaling during tail regeneration in the leopard Gecko (Eublepharis macularius). Gilbert RW, Vickaryous MK, Viloria-Petit AM. Dev Dyn 242 886-896 (2013)
  6. T Cell CX3CR1 Mediates Excess Atherosclerotic Inflammation in Renal Impairment. Dong L, Nordlohne J, Ge S, Hertel B, Melk A, Rong S, Haller H, von Vietinghoff S. J Am Soc Nephrol 27 1753-1764 (2016)
  7. Crystal structures of apo and inhibitor-bound TGFβR2 kinase domain: insights into TGFβR isoform selectivity. Tebben AJ, Ruzanov M, Gao M, Xie D, Kiefer SE, Yan C, Newitt JA, Zhang L, Kim K, Lu H, Kopcho LM, Sheriff S. Acta Crystallogr D Struct Biol 72 658-674 (2016)
  8. VEGF, FGF-2 and TGFβ expression in the normal and regenerating epidermis of geckos: implications for epidermal homeostasis and wound healing in reptiles. Subramaniam N, Petrik JJ, Vickaryous MK. J Anat 232 768-782 (2018)
  9. TGF-β sensu stricto signaling regulates skeletal morphogenesis in the sea urchin embryo. Sun Z, Ettensohn CA. Dev Biol 421 149-160 (2017)
  10. Growth differentiation factor 11 is an encephalic regionalizing factor in neural differentiated mouse embryonic stem cells. Vanbekbergen N, Hendrickx M, Leyns L. BMC Res Notes 7 766 (2014)
  11. Par6 is an essential mediator of apoptotic response to transforming growth factor beta in NMuMG immortalized mammary cells. Avery-Cooper G, Doerr M, Gilbert RW, Youssef M, Richard A, Huether P, Viloria-Petit AM. Cancer Cell Int 14 19 (2014)
  12. Autophagy-dependent regulation of tumor metastasis by myeloid cells. Jinushi M, Morita T, Xu Z, Kinoshita I, Dosaka-Akita H, Yagita H, Kawakami Y. PLoS One 12 e0179357 (2017)
  13. Dietary chlorophyllin abrogates TGFβ signaling to modulate the hallmark capabilities of cancer in an animal model of forestomach carcinogenesis. Thiyagarajan P, Kavitha K, Thautam A, Dixit M, Nagini S. Tumour Biol 35 6725-6737 (2014)
  14. Cancer Stem-Like Phenotype of Mitochondria Dysfunctional Hep3B Hepatocellular Carcinoma Cell Line. Han YS, Yi EY, Jegal ME, Kim YJ. Cells 10 1608 (2021)
  15. A Small β-Carboline Derivative "B-9-3" Modulates TGF-β Signaling Pathway Causing Tumor Regression in Vivo. Zhong H, Daoud A, Han J, An X, Qiao C, Duan L, Wang Y, Chen Z, Zhou J, Shang J. Front Pharmacol 9 788 (2018)
  16. 2D-QSAR study, molecular docking, and molecular dynamics simulation studies of interaction mechanism between inhibitors and transforming growth factor-beta receptor I (ALK5). Jiang MN, Zhou XP, Sun DR, Gao H, Zheng QC, Zhang HX, Liang D. J Biomol Struct Dyn 36 3705-3717 (2018)
  17. In Silico Analysis and Comparative Molecular Docking Study of FDA Approved Drugs with Transforming Growth Factor Beta Receptors in Oral Submucous Fibrosis. Rai A, Qazi S, Raza K. Indian J Otolaryngol Head Neck Surg 74 2111-2121 (2022)
  18. Transforming growth factor-β signalling regulates protoscolex formation in the Echinococcus multilocularis metacestode. Kaethner M, Epping K, Bernthaler P, Rudolf K, Thomann I, Leitschuh N, Bergmann M, Spiliotis M, Koziol U, Brehm K. Front Cell Infect Microbiol 13 1153117 (2023)


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