Small-molecule Inhibitors of the C-Fes Protein-tyrosine Kinase

Overview

Journal Chem Biol

Publisher Elsevier

Specialties Biochemistry
Biology
Chemistry

Date 2012 Apr 24

PMID 22520759

Citations 19

Authors

Sabine Hellwig

Chandra V Miduturu

Shigeru Kanda

Jianming Zhang

Panagis Filippakopoulos

Eidarus Salah

Xianming Deng

Hwan Geun Choi

Wenjun Zhou

Wooyoung Hur

Stefan Knapp

Nathanael S Gray

Thomas E Smithgall

Affiliations

Soon will be listed here.

Abstract

The c-Fes protein-tyrosine kinase modulates cellular signaling pathways governing differentiation, the innate immune response, and vasculogenesis. Here, we report the identification of types I and II kinase inhibitors with potent activity against c-Fes both in vitro and in cell-based assays. One of the most potent inhibitors is the previously described anaplastic lymphoma kinase inhibitor TAE684. The crystal structure of TAE684 in complex with the c-Fes SH2-kinase domain showed excellent shape complementarity with the ATP-binding pocket and a key role for the gatekeeper methionine in the inhibitory mechanism. TAE684 and two pyrazolopyrimidines with nanomolar potency against c-Fes in vitro were used to establish a role for this kinase in osteoclastogenesis, illustrating the value of these inhibitors as tool compounds to probe the diverse biological functions associated with this unique kinase.

Citing Articles

Non-Receptor Tyrosine Kinases: Their Structure and Mechanistic Role in Tumor Progression and Resistance.

Eshaq A, Flanagan T, Hassan S, Al Asheikh S, Al-Amoudi W, Santourlidis S Cancers (Basel). 2024; 16(15).

PMID: 39123481 PMC: 11311543. DOI: 10.3390/cancers16152754.

Characterization and clustering of kinase isoform expression in metastatic melanoma.

Holland D, Gotea V, Fedkenheuer K, Jaiswal S, Baugher C, Tan H PLoS Comput Biol. 2022; 18(5):e1010065.

PMID: 35560144 PMC: 9132324. DOI: 10.1371/journal.pcbi.1010065.

FER-mediated phosphorylation and PIK3R2 recruitment on IRS4 promotes AKT activation and tumorigenesis in ovarian cancer cells.

Zhang Y, Xiong X, Zhu Q, Zhang J, Chen S, Wang Y Elife. 2022; 11.

PMID: 35550247 PMC: 9098222. DOI: 10.7554/eLife.76183.

Latest perspectives of orally bioavailable 2,4-diarylaminopyrimidine analogues (DAAPalogues) as anaplastic lymphoma kinase inhibitors: discovery and clinical developments.

Latif M, Ashraf Z, Basit S, Ghaffar A, Zafar M, Saeed A RSC Adv. 2022; 8(30):16470-16493.

PMID: 35540549 PMC: 9080316. DOI: 10.1039/c8ra01934g.

Macrophages Switch to an Osteo-Modulatory Profile Upon RANKL Induction in a Medaka () Osteoporosis Model.

Phan Q, Liu R, Tan W, Imangali N, Cheong B, Schartl M JBMR Plus. 2020; 4(11):e10409.

PMID: 33210062 PMC: 7657398. DOI: 10.1002/jbm4.10409.

References

Greer P, Haigh J, Mbamalu G, Khoo W, Bernstein A, Pawson T . The Fps/Fes protein-tyrosine kinase promotes angiogenesis in transgenic mice. Mol Cell Biol. 1994; 14(10):6755-63. PMC: 359206. DOI: 10.1128/mcb.14.10.6755-6763.1994. View

Engen J, Wales T, Hochrein J, Meyn 3rd M, Ozkan S, Bahar I . Structure and dynamic regulation of Src-family kinases. Cell Mol Life Sci. 2008; 65(19):3058-73. PMC: 9357288. DOI: 10.1007/s00018-008-8122-2. View

Lerner E, Smithgall T . SH3-dependent stimulation of Src-family kinase autophosphorylation without tail release from the SH2 domain in vivo. Nat Struct Biol. 2002; 9(5):365-9. DOI: 10.1038/nsb782. View

Kanda S, Miyata Y, Kanetake H, Smithgall T . Non-receptor protein-tyrosine kinases as molecular targets for antiangiogenic therapy (Review). Int J Mol Med. 2007; 20(1):113-21. View

Zhang J, Yang P, Gray N . Targeting cancer with small molecule kinase inhibitors. Nat Rev Cancer. 2008; 9(1):28-39. DOI: 10.1038/nrc2559. View

Briggs S, Smithgall T . SH2-kinase linker mutations release Hck tyrosine kinase and transforming activities in Rat-2 fibroblasts. J Biol Chem. 1999; 274(37):26579-83. DOI: 10.1074/jbc.274.37.26579. View

Wang L, Feldman R, Shibuya M, Hanafusa H, Notter M, BALDUZZI P . Genetic structure, transforming sequence, and gene product of avian sarcoma virus UR1. J Virol. 1981; 40(1):258-67. PMC: 256615. DOI: 10.1128/JVI.40.1.258-267.1981. View

Hanahan D, Weinberg R . The hallmarks of cancer. Cell. 2000; 100(1):57-70. DOI: 10.1016/s0092-8674(00)81683-9. View

Voisset E, Lopez S, Chaix A, Georges C, Hanssens K, Prebet T . FES kinases are required for oncogenic FLT3 signaling. Leukemia. 2010; 24(4):721-8. DOI: 10.1038/leu.2009.301. View

10.

Roebroek A, Schalken J, Verbeek J, van den Ouweland A, Onnekink C, Bloemers H . The structure of the human c-fes/fps proto-oncogene. EMBO J. 1985; 4(11):2897-903. PMC: 554595. DOI: 10.1002/j.1460-2075.1985.tb04020.x. View

11.

McCoy A, Grosse-Kunstleve R, Storoni L, Read R . Likelihood-enhanced fast translation functions. Acta Crystallogr D Biol Crystallogr. 2005; 61(Pt 4):458-64. DOI: 10.1107/S0907444905001617. View

12.

Painter J, Merritt E . Optimal description of a protein structure in terms of multiple groups undergoing TLS motion. Acta Crystallogr D Biol Crystallogr. 2006; 62(Pt 4):439-50. DOI: 10.1107/S0907444906005270. View

13.

Boyle W, Simonet W, Lacey D . Osteoclast differentiation and activation. Nature. 2003; 423(6937):337-42. DOI: 10.1038/nature01658. View

14.

Itoh T, De Camilli P . BAR, F-BAR (EFC) and ENTH/ANTH domains in the regulation of membrane-cytosol interfaces and membrane curvature. Biochim Biophys Acta. 2006; 1761(8):897-912. DOI: 10.1016/j.bbalip.2006.06.015. View

15.

Rogers J, Cheng H, Smithgall T . Src homology 2 domain substitution modulates the kinase and transforming activities of the Fes protein-tyrosine kinase. Cell Growth Differ. 2000; 11(11):581-92. View

16.

Huang C, Hammond C, Bishop J . Nucleotide sequence and topography of chicken c-fps. Genesis of a retroviral oncogene encoding a tyrosine-specific protein kinase. J Mol Biol. 1985; 181(2):175-86. DOI: 10.1016/0022-2836(85)90083-x. View

17.

Hellwig S, Smithgall T . Structure and regulation of the c-Fes protein-tyrosine kinase. Front Biosci (Landmark Ed). 2011; 16(8):3146-55. DOI: 10.2741/3902. View

18.

Sadowski I, Stone J, Pawson T . A noncatalytic domain conserved among cytoplasmic protein-tyrosine kinases modifies the kinase function and transforming activity of Fujinami sarcoma virus P130gag-fps. Mol Cell Biol. 1986; 6(12):4396-408. PMC: 367222. DOI: 10.1128/mcb.6.12.4396-4408.1986. View

19.

Roodman G . Mechanisms of bone metastasis. N Engl J Med. 2004; 350(16):1655-64. DOI: 10.1056/NEJMra030831. View

20.

Murshudov G, Vagin A, Dodson E . Refinement of macromolecular structures by the maximum-likelihood method. Acta Crystallogr D Biol Crystallogr. 1997; 53(Pt 3):240-55. DOI: 10.1107/S0907444996012255. View