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4-Acyl Pyrroles as Dual BET-BRD7/9 Bromodomain Inhibitors Address BETi Insensitive Human Cancer Cell Lines.

Hügle M, Regenass P, Warstat R, Hau M, Schmidtkunz K, Lucas X, Wohlwend D, Einsle O, Jung M, Breit B, Günther S
J Med Chem 63 15603-15620 (2020)
Related entries: 6s4b, 6s6k, 6sa2, 6sa3, 6sah, 6saj, 6sb8

Cited: 7 times
EuropePMC logo PMID: 33275431

Abstract

Various malignant human diseases show disturbed signaling pathways due to increased activity of proteins within the epigenetic machinery. Recently, various novel inhibitors for epigenetic regulation have been introduced which promise a great therapeutic benefit. Inhibitors for the bromo- and extra-terminal domain (BET) family were of particular interest after inhibitors had shown a strong antiproliferative effect. More recently, the focus has increasingly shifted to bromodomains (BDs) outside the BET family. Based on previously developed inhibitors, we have optimized a small series of 4-acyl pyrroles, which we further analyzed by ITC, X-ray crystallography, selectivity studies, the NCI60 cell-panel, and GI50 determinations for several cancer cell lines. The inhibitors address both, BET and BRD7/9 BDs, with very high affinity and show a strong antiproliferative effect on various cancer cell lines that could not be observed for BD family selective inhibitors. Furthermore, a synergistic effect on breast cancer (MCF-7) and melanoma (SK-MEL-5) was proven.

Reviews citing this publication (5)

  1. Dual-target inhibitors of bromodomain and extra-terminal proteins in cancer: A review from medicinal chemistry perspectives. Feng L, Wang G, Chen Y, Chen Y, He G, Liu B, Liu J, Chiang CM, Ouyang L. Med Res Rev 42 710-743 (2022)
  2. Histone Modifications and Their Targeting in Lymphoid Malignancies. Fernández-Serrano M, Winkler R, Santos JC, Le Pannérer MM, Buschbeck M, Roué G. Int J Mol Sci 23 253 (2021)
  3. SWI/SNF Chromatin Remodeling Enzymes in Melanoma. Dreier MR, de la Serna IL. Epigenomes 6 10 (2022)
  4. Impact of Histone Modifications and Their Therapeutic Targeting in Hematological Malignancies. Markouli M, Strepkos D, Piperi C. Int J Mol Sci 23 13657 (2022)
  5. Bromodomain inhibitors and therapeutic applications. Gajjela BK, Zhou MM. Curr Opin Chem Biol 75 102323 (2023)

Articles citing this publication (2)

  1. Identification of a BAZ2A-Bromodomain Hit Compound by Fragment Growing. Dalle Vedove A, Cazzanelli G, Batiste L, Marchand JR, Spiliotopoulos D, Corsi J, D'Agostino VG, Caflisch A, Lolli G. ACS Med Chem Lett 13 1434-1443 (2022)
  2. The role of loop dynamics in the prediction of ligand-protein binding enthalpy. Çınaroğlu SS, Biggin PC. Chem Sci 14 6792-6805 (2023)


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