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Mélin L, Abdullayev S, Fnaiche A, et al. Development of LM98, a Small-Molecule TEAD Inhibitor Derived from Flufenamic Acid. ChemMedChem. 2021;16(19):2982-3002doi: 10.1002/cmdc.202100432.
Mélin, L., Abdullayev, S., Fnaiche, A., Vu, V., González Suárez, N., Zeng, H., Szewczyk, M. M., Li, F., Senisterra, G., Allali-Hassani, A., Chau, I., Dong, A., Woo, S., Annabi, B., Halabelian, L., LaPlante, S. R., Vedadi, M., Barsyte-Lovejoy, D., Santhakumar, V., & Gagnon, A. (2021). Development of LM98, a Small-Molecule TEAD Inhibitor Derived from Flufenamic Acid. ChemMedChem, 16(19), 2982-3002. https://doi.org/10.1002/cmdc.202100432
Mélin, Léa, et al. "Development of LM98, a Small-Molecule TEAD Inhibitor Derived from Flufenamic Acid." ChemMedChem vol. 16,19 (2021): 2982-3002. doi: https://doi.org/10.1002/cmdc.202100432
Mélin L, Abdullayev S, Fnaiche A, Vu V, González Suárez N, Zeng H, Szewczyk MM, Li F, Senisterra G, Allali-Hassani A, Chau I, Dong A, Woo S, Annabi B, Halabelian L, LaPlante SR, Vedadi M, Barsyte-Lovejoy D, Santhakumar V, Gagnon A. Development of LM98, a Small-Molecule TEAD Inhibitor Derived from Flufenamic Acid. ChemMedChem. 2021 Oct 06;16(19):2982-3002. doi: 10.1002/cmdc.202100432. Epub 2021 Jul 28. PMID: 34164919.
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ChemMedChem. 2021 Oct 06;16(19):2982-3002. doi: 10.1002/cmdc.202100432. Epub 2021 Jul 28.

Development of LM98, a Small-Molecule TEAD Inhibitor Derived from Flufenamic Acid.

ChemMedChem

Léa Mélin, Shuay Abdullayev, Ahmed Fnaiche, Victoria Vu, Narjara González Suárez, Hong Zeng, Magdalena M Szewczyk, Fengling Li, Guillermo Senisterra, Abdellah Allali-Hassani, Irene Chau, Aiping Dong, Simon Woo, Borhane Annabi, Levon Halabelian, Steven R LaPlante, Masoud Vedadi, Dalia Barsyte-Lovejoy, Vijayaratnam Santhakumar, Alexandre Gagnon

Affiliations

  1. Département de chimie, Université du Québec à Montréal, C.P. 8888, Succ. Centre-Ville, Montréal, QC, H3C 3P8, Canada.
  2. Structural Genomics Consortium, University of Toronto, 101 College St. MaRS South Tower, Toronto, ON, M5G 1 L7, Canada.
  3. INRS-Centre Armand Frappier Santé Biotechnologie, Université du Québec, 531 Boulevard des Prairies, Laval, QC, H7V 1B7, Canada.
  4. Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, M5S 1 A8, Canada.

PMID: 34164919 DOI: 10.1002/cmdc.202100432

Abstract

The YAP-TEAD transcriptional complex is responsible for the expression of genes that regulate cancer cell growth and proliferation. Dysregulation of the Hippo pathway due to overexpression of TEAD has been reported in a wide range of cancers. Inhibition of TEAD represses the expression of associated genes, demonstrating the value of this transcription factor for the development of novel anti-cancer therapies. We report herein the design, synthesis and biological evaluation of LM98, a flufenamic acid analogue. LM98 shows strong affinity to TEAD, inhibits its autopalmitoylation and reduces the YAP-TEAD transcriptional activity. Binding of LM98 to TEAD was supported by

© 2021 Wiley-VCH GmbH.

Keywords: Flufenamic acid; Hippo pathway; SAR; TEAD; palmitic acid

References

  1. K. Harvey, N. Tapon, Nat. Rev. Cancer 2007, 7, 182-191. - PubMed
  2. L. Cairns, T. Tran, J. M. Kavran, ACS Chem. Biol. 2017, 12, 601-610. - PubMed
  3. S. Piccolo, S. Dupont, M. Cordenonsi, Physiol. Rev. 2014, 94, 1287-1312. - PubMed
  4. M. K. Kim, J. W. Jang, S. C. Bae, BMB Rep. 2018, 51, 126-133. - PubMed
  5. S. Strano, E. Munarriz, M. Rossi, L. Castagnoli, Y. Shaul, A. Sacchi, M. Oren, M. Sudol, G. Cesareni, G. Blandino, J. Biol. Chem. 2001, 276, 15164-15173. - PubMed
  6. H. Zhang, H. A. Pasolli, E. Fuchs, Proc. Natl. Acad. Sci. USA 2011, 108, 2270-2275. - PubMed
  7. B. Zhao, L. Li, Q. Lei, K. L. Guan, Genes Dev. 2010, 24, 862-874. - PubMed
  8. A. V. Pobbati, W. Hong, Cancer Biol. Ther. 2013, 14, 390-398. - PubMed
  9. M. Z. Xu, S. W. Chan, A. M. Liu, K. F. Wong, S. T. Fan, J. Chen, R. T. Poon, L. Zender, S. W. Lowe, W. Hong, J. M. Luk, Oncogene 2011, 30, 1229-1240. - PubMed
  10. D. Pan, Dev. Cell. 2010, 19, 491-505. - PubMed
  11. A. A. Ahmed, A. D. Mohamed, M. Gener, W. Li, E. Taboada, Mol. Cell. Oncol. 2017, 4, e1295127. - PubMed
  12. M. Corvaisier, M. Bauzone, F. Corfiotti, F. Renaud, M. El Amrani, D. Monté, S. Truant, E. Leteurtre, P. Formstecher, I. Van Seuningen, C. Gespach, G. Huet, Oncotarget 2016, 7, 56699-56712. - PubMed
  13. L. Guo, L. Teng, Int. J. Oncol. 2015, 46, 1444-1452. - PubMed
  14. J. F. Knight, C. J. Shepherd, S. Rizzo, D. Brewer, S. Jhavar, A. R. Dodson, C. S. Cooper, R. Eeles, A. Falconer, G. Kovacs, M. D. Garrett, A. R. Norman, J. Shipley, D. L. Hudson, Br. J. Cancer. 2008, 99, 1849-1858. - PubMed
  15. T. Hucl, J. R. Brody, E. Gallmeier, C. A. Iacobuzio-Donahue, I. K. Farrance, S. E. Kern, Cancer Res. 2007, 67, 9055-9065. - PubMed
  16. Y. Liu, G. Wang, Y. Yang, Z. Mei, Z. Liang, A. Cui, T. Wu, C. Y. Liu, L. Cui, Oncogene 2016, 35, 2789-2800. - PubMed
  17. B. Lim, J. L. Park, H. J. Kim, Y. K. Park, J. H. Kim, H. A. Sohn, S. M. Noh, K. S. Song, W. H. Kim, Y. S. Kim, S. Y. Kim, Carcinogenesis 2014, 35, 1020-1027. - PubMed
  18. R. Johnson, G. Halder, Nat. Rev. Drug Discovery 2014, 13, 63-79. - PubMed
  19. B. Zhao, X. Ye, J. Yu, L. Li, W. Li, S. Li, J. Yu, J. D. Lin, C. Y. Wang, A. M. Chinnaiyan, Z. C. Lai, K. L. Guan Genes Dev. 2008, 22, 1962-1971. - PubMed
  20. B. Zhao, J. Kim, X. Ye, Z. C. Lai, K. L. Guan, Cancer Res. 2009, 69, 1089-1098. - PubMed
  21. J. Dong, G. Feldmann, J. Huang, S. Wu, N. Zhang, S. A. Comerford, M. F. Gayyed, R. A. Anders, A. Maitra, D. Pan, Cell. 2007, 130, 1120-1133. - PubMed
  22. F. Zanconato, M. Cordenonsi, S. Piccolo, Cancer Cell 2016, 29, 783-803. - PubMed
  23. J. S. A. Warren, Y. Xiao, J. M. Lamar, Cancers 2018, 10, 115-151. - PubMed
  24. Y. Liu-Chittenden, B. Huang, J. Sup Shim, Q. Chen, S.-J. Lee, R. A. Anders, J. O. Liu, D. Pan, Genes Dev. 2012, 26, 1300-1305. - PubMed
  25. Z. Li, B. Zhao, P. Wang, F. Chen, Z. Dong, H. Yang, K. L. Guan, Y. Xu, Genes Dev. 2010, 24, 235-240. - PubMed
  26. Z. Zhou, T. Hu, Z. Xu, Z. Lin, Z. Zhang, T. Feng, L. Zhu, Y. Rong, H. Shen, J. M. Luk, X. Zhang, N. Qin, FASEB J. 2015, 29, 724-732. - PubMed
  27. Z. Zhang, Z. Lin, Z. Zhou, H. C. Shen, S. F. Yan, A. V. Mayweg, Z. Xu, N. Qin, J. C. Wong, Z. Zhang, Y. Rong, D. C. Fry, T. Hu, ACS Med. Chem. Lett. 2014, 5, 993-998. - PubMed
  28. P. Furet, B. Salem, Y. Mesrouze, T. Schmelzle, I. Lewis, J. Kallen, P. Chène, Bioorg. Med. Chem. Lett. 2019, 29, 2316-2319. - PubMed
  29. Z. R. Crook, G. P. Sevilla, D. Friend, M. Y. Brusniak, A. D. Bandaranayake, M. Clarke, M. Gewe, A. J. Mhyre, D. Baker, R. K. Strong, P. Bradley, J. M. Olson, Nat. Commun. 2017, 8, 2244-2258. - PubMed
  30. S. Jiao, H. Wang, Z. Shi, A. Dong, W. Zhang, X. Song, F. He, Y. Wang, Z. Zhang, W. Wang, X. Wang, T. Guo, P. Li, Y. Zhao, H. Ji, L. Zhang, Z. Zhou, Cancer Cell 2014, 25, 166-180. - PubMed
  31. F. Gibault, M. Coevoet, M. Sturbaut, A. Farce, N. Renault, F. Allemand, J.-F. Guichou, A.-S. Drucbert, C. Foulon, R. Magnez, X. Thuru, M. Corvaisier, G. Huet, P. Chavatte, P. Melnyk, F. Bailly, P. Cotelle, Cancers 2018, 10, 140-153. - PubMed
  32. S. A. Smith, R. B. Sessions, D. K. Shoemark, C. Williams, R. Ebrahimighaei, M. C. McNeill, M. P. Crump, T. R. McKay, G. Harris, A. C. Newby, M. Bond, J. Med. Chem. 2019, 62, 1291-1305. - PubMed
  33. A. V. Pobbati, B. P. Rubin, Molecules 2020, 25, 6001-6017. - PubMed
  34. Y. Li, S. Liu, E. Y. Ng, R. Li, A. Poulsen, J. Hill, A. V. Pobbati, A. W. Hung, W. Hong, T. H. Keller, C. Kang, Biochem. J. 2018, 475, 2043-2055. - PubMed
  35. P. Chan, X. Han, B. Zheng, M. DeRan, J. Yu, G. K. Jarugumilli, H. Deng, D. Pan, X. Luo, X. Wu, Nat. Chem. Biol. 2016, 12, 282-289. - PubMed
  36. C. L. Noland, S. Gierke, P. D. Schnier, J. Murray, W. N. Sandoval, M. Sagolla, A. Dey, R. N. Hannoush, W. J. Fairbrother, C. N. Cunningham, Structure 2016, 24, 179-186. - PubMed
  37. Y. Mesrouze, M. Meyerhofer, F. Bokhovchuk, P. Fontana, C. Zimmermann, T. Martin, C. Delaunay, A. Izaac, J. Kallen, T. Schmelzle, D. Erdmann, P. Chène, Protein Sci. 2017, 26, 2399-2409. - PubMed
  38. X. Wu, International Patent WO 2017/053706 A1, 2017. - PubMed
  39. N. G. Kim, B. M. Gumbiner, Proc. Natl. Acad. Sci. USA 2019, 116, 9877-9882. - PubMed
  40. A. V. Pobbati, X. Han, A. W. Hung, S. Weiguang, N. Huda, G. Y. Chen, C. Kang, C. S. B. Chia, X. Luo, W. Hong, A. Poulsen, Structure 2015, 23, 2076-2086. - PubMed
  41. M. Barth, S. Contal, J. L. Junien, C. Massardier, C. Montalbetti, A. Soude, International Patent WO 2020/070181 A1, 2020. - PubMed
  42. J. K. Holden, J. J. Crawford, C. L. Noland, S. Schmidt, J. R. Zbieg, J. A. Lacap, R. Zang, G. M. Miller, Y. Zhang, P. Beroza, R. Reja, W. Lee, J. Y. W. K. Tom, R. Fong, M. Steffek, S. Clausen, T. J. Hagenbeek, T. Hu, Z. Zhou, H. C. Shen, C. N. Cunningham, Cell Rep. 2020, 31, 107809. - PubMed
  43. V. B. K. Kunig, M. Potowski, M. Akbarzadeh, M. K. Škopić, D. Dos Santos Smith, L. Arendt, I. Dormuth, H. Adihou, B. Andlovic, H. Karatas, S. Shaabani, T. Zarganes-Tzitzikas, C. G. Neochoritis, R. Zhang, M. Groves, S. M. Guéret, C. Ottmann, J. Rahnenführer, R. Fried, A. Dömling, A. Brunschweiger, Angew. Chem. Int. Ed. Engl. 2020, 59, 20338-20342. - PubMed
  44. W. Lu, J. Wang, Y. Li, H. Tao, H. Xiong, F. Lian, J. Gao, H. Ma, T. Lu, D. Zhang, X. Ye, H. Ding, L. Yue, Y. Zhang, H. Tang, N. Zhang, Y. Yang, H. Jiang, K. Chen, B. Zhou, C. Luo, Eur. J. Med. Chem. 2019, 184, 111767. - PubMed
  45. K. Bum-Erdene, D. Zhou, H. Gonzalez-Gutierrez, M. K. Ghozayel, Y. Si, D. Xu, H. E. Shannon, B. J. Bailey, T. W. Corson, K. E. Pollok, C. D. Wells, S. O. Meroueh, Cell Chem. Biol. 2019, 26, 378-389. - PubMed
  46. A. V. Pobbati, T. Mejuch, S. Chakraborty, H. Karatas, S. R. Bharath, S. M. Guéret, P. A. Goy, G. Hahne, A. Pahl, S. Sievers, E. Guccione, H. Song, H. Waldmann, W. Hong, ACS Chem. Biol. 2019, 14, 2909-2921. - PubMed
  47. F. H. Niesen, H. Berglund, M. Vedadi, Nat. Protoc. 2007, 2, 2212-2221. - PubMed
  48. M. Vedadi, F. H. Niesen, A. Allali-Hassani, O. Y. Fedorov, P. J. Finerty Jr, G. A. Wasney, R. Yeung, C. Arrowsmith, L. J. Ball, H. Berglund, R. Hui, B. D. Marsden, P. Nordlund, M. Sundstrom, J. Weigelt, A. M. Edwards, Proc. Natl. Acad. Sci. USA 2006, 103, 15835-15840. - PubMed
  49. N. Igoe, E. D. Bayle, C. Tallant, O. Fedorov, J. C. Meier, P. Savitsky, C. Rogers, Y. Morias, S. Scholze, H. Boyd, D. Cunoosamy, D. M. Andrews, A. Cheasty, P. E. Brennan, S. Müller, S. Knapp, P. V. Fish, J. Med. Chem. 2017, 60, 6998-7011. - PubMed
  50. A. N. Bullock, J. E. Debreczeni, O. Y. Fedorov, A. Nelson, B. D. Marsden, S. Knapp, J. Med. Chem. 2005, 48, 7604-7614. - PubMed
  51. A. M. Omar, M. A. Elfaky, S. T. Arold, S. H. Soror, M. T. Khayat, H. Z. Asfour, F. H. Bamane, M. E. El-Araby, Biomolecules 2020, 10, 479-501. - PubMed
  52. U. S. Hameed, I. Haider, M. Jamil, B. A. Kountche, X. Guo, R. A. Zarban, D. Kim, A. Al-Babili, S. T. Arold, EMBO Rep. 2018, 19, e45619. - PubMed
  53. T. Sugiki, K. Furuita, T. Fujiwara, C. Kojima, Molecules 2018, 23, 148-174. - PubMed
  54. C. Dalvit, A. Vulpetti, J. Med. Chem. 2019, 62, 2218-2244. - PubMed
  55. S. Akoka, L. Barantin, M. Trierweiler, Anal. Chem. 1999, 71, 2554-2557. - PubMed
  56. T. Machleidt, C. C. Woodroofe, M. K. Schwinn, J. Méndez, M. B. Robers, K. Zimmerman, P. Otto, D. L. Daniels, T. A. Kirkland, K. V. Wood, ACS Chem. Biol. 2015, 10, 1797-1804. - PubMed
  57. S. Dupont, L. Morsut, M. Aragona, E. Enzo, S. Giulitti, M. Cordenonsi, F. Zanconato, J. Le Digabel, M. Forcato, S. Bicciato, N. Elvassore, S. Piccolo, Nature 2011, 474, 179-183. - PubMed
  58. H. Andersson, H. Demaegdt, G. Vauquelin, G. Lindeberg, A. Karlén, M. Hallberg, Bioorg. Med. Chem. 2008, 16, 6924-6935. - PubMed
  59. G. Ortar, M. Grazia Cascio, L. De Petrocellis, E. Morera, F. Rossi, A. Schiano-Moriello, M. Nalli, V. de Novellis, D. F. Woodward, S. Maione, V. Di Marzo, J. Med. Chem. 2007, 50, 6554-6569. - PubMed
  60. B. Ringstrand, M. Oltmanns, J. A. Batt, A. Jankowiak, R. P. Denicola, P. Kaszynski, Beilstein J. Org. Chem. 2011, 7, 386-393. - PubMed
  61. V. P. Prasad, S. Wagner, P. Keul, S. Hermann, B. Levkau, M. Schäfers, G. Haufe, Bioorg. Med. Chem. 2014, 22, 5168-5181. - PubMed
  62. C. Féau, L. A. Arnold, A. Kosinski, F. Zhu, M. Connelly, R. K. Guy, ACS Chem. Biol. 2009, 4, 834-843. - PubMed
  63. T. S. Mei, R. Giri, N. Maugel, J. Q. Yu, Angew. Chem. Int. Ed. Engl. 2008, 47, 5215-5219. - PubMed
  64. D. S. Zurabishvili, M. O. Lomidze, S. A. Samsoniya, A. Wesquet, U. Kazmaier, Chem. Heterocycl. Compd. 2008, 44, 941-949. - PubMed
  65. A. Koperniku, A. S. Foscolos, I. Papanastasiou, G. B. Foscolos, A. Tsotinis, D. Schols, Lett. Org. Chem. 2016, 13, 171-176. - PubMed
  66. C. M. Rudzinski, A. M. Young, D. G. Nocera, J. Am. Chem. Soc. 2002, 124, 1723-1727. - PubMed

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