Characterization of a dual BET/HDAC inhibitor for treatment of pancreatic ductal adenocarcinoma.

Autor: Zhang X; Institute for Developmental Cancer Therapeutics, West German Cancer Center, University Medicine Essen, Essen, Germany.; Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, partner site University Hospital Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany., Zegar T; Institute for Developmental Cancer Therapeutics, West German Cancer Center, University Medicine Essen, Essen, Germany.; Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, partner site University Hospital Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany., Weiser T; Structural Genomics Consortium, Buchmann Institute for Life Sciences, Goethe University Frankfurt, Frankfurt, Germany.; Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Frankfurt, Germany.; German Cancer Network (DKTK), Frankfurt, Germany., Hamdan FH; Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany.; Gene Regulatory Mechanisms and Molecular Epigenetics Lab, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA., Berger BT; Structural Genomics Consortium, Buchmann Institute for Life Sciences, Goethe University Frankfurt, Frankfurt, Germany.; Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Frankfurt, Germany., Lucas R; Structural Genomics Consortium, Buchmann Institute for Life Sciences, Goethe University Frankfurt, Frankfurt, Germany.; Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Frankfurt, Germany.; German Cancer Network (DKTK), Frankfurt, Germany., Balourdas DI; Structural Genomics Consortium, Buchmann Institute for Life Sciences, Goethe University Frankfurt, Frankfurt, Germany.; Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Frankfurt, Germany., Ladigan S; Department of Molecular Gastrointestinal Oncology, Ruhr-University Bochum, Bochum, Germany.; Department of Internal Medicine, Knappschaftskrankenhaus Bochum, Ruhr-University of Bochum, Bochum, Germany., Cheung PF; Institute for Developmental Cancer Therapeutics, West German Cancer Center, University Medicine Essen, Essen, Germany.; Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, partner site University Hospital Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany., Liffers ST; Institute for Developmental Cancer Therapeutics, West German Cancer Center, University Medicine Essen, Essen, Germany.; Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, partner site University Hospital Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany., Trajkovic-Arsic M; Institute for Developmental Cancer Therapeutics, West German Cancer Center, University Medicine Essen, Essen, Germany.; Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, partner site University Hospital Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany., Scheffler B; DKFZ Division of Translational Neurooncology, West German Cancer Center, DKTK partner site University Hospital Essen, Essen, Germany., Joerger AC; Structural Genomics Consortium, Buchmann Institute for Life Sciences, Goethe University Frankfurt, Frankfurt, Germany.; Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Frankfurt, Germany.; German Cancer Network (DKTK), Frankfurt, Germany., Hahn SA; Department of Molecular Gastrointestinal Oncology, Ruhr-University Bochum, Bochum, Germany., Johnsen SA; Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany.; Gene Regulatory Mechanisms and Molecular Epigenetics Lab, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA., Knapp S; Structural Genomics Consortium, Buchmann Institute for Life Sciences, Goethe University Frankfurt, Frankfurt, Germany.; Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Frankfurt, Germany.; German Cancer Network (DKTK), Frankfurt, Germany., Siveke JT; Institute for Developmental Cancer Therapeutics, West German Cancer Center, University Medicine Essen, Essen, Germany.; Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, partner site University Hospital Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany.
Jazyk: angličtina
Zdroj: International journal of cancer [Int J Cancer] 2020 Nov 15; Vol. 147 (10), pp. 2847-2861. Date of Electronic Publication: 2020 Jun 29.
DOI: 10.1002/ijc.33137
Abstrakt: Pancreatic ductal adenocarcinoma (PDAC) is resistant to virtually all chemo- and targeted therapeutic approaches. Epigenetic regulators represent a novel class of drug targets. Among them, BET and HDAC proteins are central regulators of chromatin structure and transcription, and preclinical evidence suggests effectiveness of combined BET and HDAC inhibition in PDAC. Here, we describe that TW9, a newly generated adduct of the BET inhibitor (+)-JQ1 and class I HDAC inhibitor CI994, is a potent dual inhibitor simultaneously targeting BET and HDAC proteins. TW9 has a similar affinity to BRD4 bromodomains as (+)-JQ1 and shares a conserved binding mode, but is significantly more active in inhibiting HDAC1 compared to the parental HDAC inhibitor CI994. TW9 was more potent in inhibiting tumor cell proliferation compared to (+)-JQ1, CI994 alone or combined treatment of both inhibitors. Sequential administration of gemcitabine and TW9 showed additional synergistic antitumor effects. Microarray analysis revealed that dysregulation of a FOSL1-directed transcriptional program contributed to the antitumor effects of TW9. Our results demonstrate the potential of a dual chromatin-targeting strategy in the treatment of PDAC and provide a rationale for further development of multitarget inhibitors.
(© 2020 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)
Databáze: MEDLINE
Externí odkaz: