TY  - JOUR
A1  - Zhang, Xin
A1  - Zegar, Tim
A1  - Weiser, Tim
A1  - Hamdan, Feda' Hisham Moh'd
A1  - Berger, Benedict-Tilman
A1  - Lucas, Romain
A1  - Balourdas, Dimitrios‐IIias
A1  - Ladigan, Swetlana
A1  - Cheung, Phyllis F.
A1  - Liffers, Sven‐Thorsten
A1  - Trajkovic‐Arsic, Marija
A1  - Scheffler, Björn
A1  - Jörger, Andreas C.
A1  - Hahn, Stephan A.
A1  - Johnsen, Steven A.
A1  - Knapp, Stefan
A1  - Siveke, Jens
T1  - Characterization of a dual BET/HDAC inhibitor for treatment of pancreatic ductal adenocarcinoma
T2  - International Journal of Cancer
N2  - 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.
KW  - BET inhibitor
KW  - combined therapy
KW  - dual BET/HDAC inhibitor
KW  - HDAC inhibitor
KW  - pancreatic ductal adenocarcinoma
Y1  - 2020
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/56509
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-565092
SN  - 1097-0215
SN  - 0020-7136
VL  - 147
IS  - 10
SP  - 2847
EP  - 2861
PB  - Wiley-Liss
CY  - Bognor Regis
ER  -