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Multidentate small-molecule inhibitors of vaccinia H1-related (VHR) phosphatase decrease proliferation of cervix cancer cells.

Wu S, Vossius S, Rahmouni S, Miletic AV, Vang T, Vazquez-Rodriguez J, Cerignoli F, Arimura Y, Williams S, Hayes T, Moutschen M, Vasile S, Pellecchia M, Mustelin T, Tautz L
J Med Chem 52 6716-23 (2009)
Cited: 32 times
EuropePMC logo PMID: 19888758

Abstract

Loss of VHR phosphatase causes cell cycle arrest in HeLa carcinoma cells, suggesting that VHR inhibition may be a useful approach to halt the growth of cancer cells. We recently reported that VHR is upregulated in several cervix cancer cell lines as well as in carcinomas of the uterine cervix. Here we report the development of multidentate small-molecule inhibitors of VHR that inhibit its enzymatic activity at nanomolar concentrations and exhibit antiproliferative effects on cervix cancer cells. Chemical library screening was used to identify hit compounds, which were further prioritized in profiling and kinetic experiments. SAR analysis was applied in the search for analogs with improved potency and selectivity, resulting in the discovery of novel inhibitors that are able to interact with both the phosphate-binding pocket and several distinct hydrophobic regions within VHR's active site. This multidentate binding mode was confirmed by X-ray crystallography. The inhibitors decreased the proliferation of cervix cancer cells, while growth of primary normal keratinocytes was not affected. These compounds may be a starting point to develop drugs for the treatment of cervical cancer.

Reviews - 3f81 mentioned but not cited (2)

  1. Critical Roles of Dual-Specificity Phosphatases in Neuronal Proteostasis and Neurological Diseases. Bhore N, Wang BJ, Chen YW, Liao YF. Int J Mol Sci 18 E1963 (2017)
  2. Health Benefits and Pharmacological Properties of Stigmasterol. Bakrim S, Benkhaira N, Bourais I, Benali T, Lee LH, El Omari N, Sheikh RA, Goh KW, Ming LC, Bouyahya A. Antioxidants (Basel) 11 1912 (2022)

Articles - 3f81 mentioned but not cited (6)

  1. Multidentate small-molecule inhibitors of vaccinia H1-related (VHR) phosphatase decrease proliferation of cervix cancer cells. Wu S, Vossius S, Rahmouni S, Miletic AV, Vang T, Vazquez-Rodriguez J, Cerignoli F, Arimura Y, Williams S, Hayes T, Moutschen M, Vasile S, Pellecchia M, Mustelin T, Tautz L. J Med Chem 52 6716-6723 (2009)
  2. Allosteric Impact of the Variable Insert Loop in Vaccinia H1-Related (VHR) Phosphatase. Beaumont VA, Reiss K, Qu Z, Allen B, Batista VS, Loria JP. Biochemistry 59 1896-1908 (2020)
  3. Structural analysis of human dual-specificity phosphatase 22 complexed with a phosphotyrosine-like substrate. Lountos GT, Cherry S, Tropea JE, Waugh DS. Acta Crystallogr F Struct Biol Commun 71 199-205 (2015)
  4. The dipeptidyl peptidase IV inhibitors vildagliptin and K-579 inhibit a phospholipase C: a case of promiscuous scaffolds in proteins. Chakraborty S, Rendón-Ramírez A, Ásgeirsson B, Dutta M, Ghosh AS, Oda M, Venkatramani R, Rao BJ, Dandekar AM, Goñi FM. F1000Res 2 286 (2013)
  5. Molecular Modeling and In Vitro Evaluation of Piplartine Analogs against Oral Squamous Cell Carcinoma. Silva RHN, Machado TQ, da Fonseca ACC, Tejera E, Perez-Castillo Y, Robbs BK, de Sousa DP. Molecules 28 1675 (2023)
  6. Synthesis of Pyrrolo[3,4-b]pyridin-5-ones via Ugi-Zhu Reaction and In Vitro-In Silico Studies against Breast Carcinoma. Morales-Salazar I, Garduño-Albino CE, Montes-Enríquez FP, Nava-Tapia DA, Navarro-Tito N, Herrera-Zúñiga LD, González-Zamora E, Islas-Jácome A. Pharmaceuticals (Basel) 16 1562 (2023)


Reviews citing this publication (9)

  1. Small molecule tools for functional interrogation of protein tyrosine phosphatases. He R, Zeng LF, He Y, Zhang S, Zhang ZY. FEBS J 280 731-750 (2013)
  2. The regulatory roles of phosphatases in cancer. Stebbing J, Lit LC, Zhang H, Darrington RS, Melaiu O, Rudraraju B, Giamas G. Oncogene 33 939-953 (2014)
  3. Dual-Specificity Phosphatases in Immunity and Infection: An Update. Lang R, Raffi FAM. Int J Mol Sci 20 E2710 (2019)
  4. Dual-specificity phosphatases as molecular targets for inhibition in human disease. Ríos P, Nunes-Xavier CE, Tabernero L, Köhn M, Pulido R. Antioxid Redox Signal 20 2251-2273 (2014)
  5. VHR/DUSP3 phosphatase: structure, function and regulation. Pavic K, Duan G, Köhn M. FEBS J 282 1871-1890 (2015)
  6. Perspective: Tyrosine phosphatases as novel targets for antiplatelet therapy. Tautz L, Senis YA, Oury C, Rahmouni S. Bioorg Med Chem 23 2786-2797 (2015)
  7. pCAP-based peptide substrates: the new tool in the box of tyrosine phosphatase assays. Stanford SM, Krishnamurthy D, Kulkarni RA, Karver CE, Bruenger E, Walker LM, Ma CT, Chung TD, Sergienko E, Bottini N, Barrios AM. Methods 65 165-174 (2014)
  8. Mimicking/extracting structure and functions of natural products: synthetic approaches that address unexplored needs in chemical biology. Hirai G. Chem Rec 15 445-456 (2015)
  9. Pentagalloyl Glucose: A Review of Anticancer Properties, Molecular Targets, Mechanisms of Action, Pharmacokinetics, and Safety Profile. Wen C, Dechsupa N, Yu Z, Zhang X, Liang S, Lei X, Xu T, Gao X, Hu Q, Innuan P, Kantapan J, Lü M. Molecules 28 4856 (2023)

Articles citing this publication (15)

  1. Diabetes reversal by inhibition of the low-molecular-weight tyrosine phosphatase. Stanford SM, Aleshin AE, Zhang V, Ardecky RJ, Hedrick MP, Zou J, Ganji SR, Bliss MR, Yamamoto F, Bobkov AA, Kiselar J, Liu Y, Cadwell GW, Khare S, Yu J, Barquilla A, Chung TDY, Mustelin T, Schenk S, Bankston LA, Liddington RC, Pinkerton AB, Bottini N. Nat Chem Biol 13 624-632 (2017)
  2. Discovery of a novel series of inhibitors of lymphoid tyrosine phosphatase with activity in human T cells. Stanford SM, Krishnamurthy D, Falk MD, Messina R, Debnath B, Li S, Liu T, Kazemi R, Dahl R, He Y, Yu X, Chan AC, Zhang ZY, Barrios AM, Woods VL, Neamati N, Bottini N. J Med Chem 54 1640-1654 (2011)
  3. Dual-specificity phosphatase 3 deficiency or inhibition limits platelet activation and arterial thrombosis. Musumeci L, Kuijpers MJ, Gilio K, Hego A, Théâtre E, Maurissen L, Vandereyken M, Diogo CV, Lecut C, Guilmain W, Bobkova EV, Eble JA, Dahl R, Drion P, Rascon J, Mostofi Y, Yuan H, Sergienko E, Chung TD, Thiry M, Senis Y, Moutschen M, Mustelin T, Lancellotti P, Heemskerk JW, Tautz L, Oury C, Rahmouni S. Circulation 131 656-668 (2015)
  4. Using small molecules to target protein phosphatases. Vintonyak VV, Waldmann H, Rauh D. Bioorg Med Chem 19 2145-2155 (2011)
  5. DUSP3/VHR is a pro-angiogenic atypical dual-specificity phosphatase. Amand M, Erpicum C, Bajou K, Cerignoli F, Blacher S, Martin M, Dequiedt F, Drion P, Singh P, Zurashvili T, Vandereyken M, Musumeci L, Mustelin T, Moutschen M, Gilles C, Noel A, Rahmouni S. Mol Cancer 13 108 (2014)
  6. Development of a Vaccinia H1-related (VHR) phosphatase inhibitor with a nonacidic phosphate-mimicking core structure. Hirai G, Tsuchiya A, Koyama Y, Otani Y, Oonuma K, Dodo K, Simizu S, Osada H, Sodeoka M. ChemMedChem 6 617-622 (2011)
  7. NMR-based design and evaluation of novel bidentate inhibitors of the protein tyrosine phosphatase YopH. Leone M, Barile E, Vazquez J, Mei A, Guiney D, Dahl R, Pellecchia M. Chem Biol Drug Des 76 10-16 (2010)
  8. Neighbours of cancer-related proteins have key influence on pathogenesis and could increase the drug target space for anticancer therapies. Módos D, Bulusu KC, Fazekas D, Kubisch J, Brooks J, Marczell I, Szabó PM, Vellai T, Csermely P, Lenti K, Bender A, Korcsmáros T. NPJ Syst Biol Appl 3 2 (2017)
  9. A selective Seoul-Fluor-based bioprobe, SfBP, for vaccinia H1-related phosphatase--a dual-specific protein tyrosine phosphatase. Jeong MS, Kim E, Kang HJ, Choi EJ, Cho AR, Chung SJ, Park SB. Chem Commun (Camb) 48 6553-6555 (2012)
  10. Development of a High-Throughput Biochemical Assay to Screen for Inhibitors of Aerobactin Synthetase IucA. Bailey DC, Buckley BP, Chernov MV, Gulick AM. SLAS Discov 23 1070-1082 (2018)
  11. Inhibition of the Hematopoietic Protein Tyrosine Phosphatase by Phenoxyacetic Acids. Bobkova EV, Liu WH, Colayco S, Rascon J, Vasile S, Gasior C, Critton DA, Chan X, Dahl R, Su Y, Sergienko E, Chung TD, Mustelin T, Page R, Tautz L. ACS Med Chem Lett 2 113-118 (2011)
  12. Natural products with protein tyrosine phosphatase inhibitory activity. Carr G, Berrue F, Klaiklay S, Pelletier I, Landry M, Kerr RG. Methods 65 229-238 (2014)
  13. Design and NMR studies of cyclic peptides targeting the N-terminal domain of the protein tyrosine phosphatase YopH. Leone M, Barile E, Dahl R, Pellecchia M. Chem Biol Drug Des 77 12-19 (2011)
  14. RE12 derivatives displaying Vaccinia H1-related phosphatase (VHR) inhibition in the presence of detergent and their anti-proliferative activity against HeLa cells. Thuaud F, Kojima S, Hirai G, Oonuma K, Tsuchiya A, Uchida T, Tsuchimoto T, Sodeoka M. Bioorg Med Chem 22 2771-2782 (2014)
  15. Functional Analysis of Protein Tyrosine Phosphatases in Thrombosis and Hemostasis. Rahmouni S, Hego A, Delierneux C, Wéra O, Musumeci L, Tautz L, Oury C. Methods Mol Biol 1447 301-330 (2016)


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