TY - JOUR
T1 - Novel Pyrrolopyridone Bromodomain and Extra-Terminal Motif (BET) Inhibitors Effective in Endocrine-Resistant ER+ Breast Cancer with Acquired Resistance to Fulvestrant and Palbociclib
AU - Li, Yangfeng
AU - Zhao, Jiong
AU - Gutgesell, Lauren M.
AU - Shen, Zhengnan
AU - Ratia, Kiira
AU - Dye, Katherine
AU - Dubrovskyi, Oleksii
AU - Zhao, Huiping
AU - Huang, Fei
AU - Tonetti, Debra A.
AU - Thatcher, Gregory R.J.
AU - Xiong, Rui
N1 - Funding Information:
The manuscript was written and the research directed by R.X. and G.R.J.T. Drug design and synthesis was directed by R.X. The largest contribution to synthesis was from Y.L. and R.X. Intermediate synthesis, scale-up, synthetic optimization, and purification were supported by Z.S. Cell line and bioassay development was led by J.Z. and R.X. Animal study was led by D.A.T. and J.Z. Biological support was provided by L.M.G. and F.H. PK was supported by K.D. and O.D. X-ray cocrystal structure was led by K.R. All authors have given approval to the final version of the manuscript.
Publisher Copyright:
Copyright © 2020 American Chemical Society.
PY - 2020/7/9
Y1 - 2020/7/9
N2 - Acquired resistance to fulvestrant and palbociclib is a new challenge to treatment of estrogen receptor positive (ER+) breast cancer. ER is expressed in most resistance settings; thus, bromodomain and extra-terminal protein inhibitors (BETi) that target BET-amplified ER-mediated transcription have therapeutic potential. Novel pyrrolopyridone BETi leveraged novel interactions with L92/L94 confirmed by a cocrystal structure of 27 with BRD4. Optimization of BETi using growth inhibition in fulvestrant-resistant (MCF-7:CFR) cells was confirmed in endocrine-resistant, palbociclib-resistant, and ESR1 mutant cell lines. 27 was more potent in MCF-7:CFR cells than six BET inhibitors in clinical trials. Transcriptomic analysis differentiated 27 from the benchmark BETi, JQ-1, showing downregulation of oncogenes and upregulation of tumor suppressors and apoptosis. The therapeutic approach was validated by oral administration of 27 in orthotopic xenografts of endocrine-resistant breast cancer in monotherapy and in combination with fulvestrant. Importantly, at an equivalent dose in rats, thrombocytopenia was mitigated.
AB - Acquired resistance to fulvestrant and palbociclib is a new challenge to treatment of estrogen receptor positive (ER+) breast cancer. ER is expressed in most resistance settings; thus, bromodomain and extra-terminal protein inhibitors (BETi) that target BET-amplified ER-mediated transcription have therapeutic potential. Novel pyrrolopyridone BETi leveraged novel interactions with L92/L94 confirmed by a cocrystal structure of 27 with BRD4. Optimization of BETi using growth inhibition in fulvestrant-resistant (MCF-7:CFR) cells was confirmed in endocrine-resistant, palbociclib-resistant, and ESR1 mutant cell lines. 27 was more potent in MCF-7:CFR cells than six BET inhibitors in clinical trials. Transcriptomic analysis differentiated 27 from the benchmark BETi, JQ-1, showing downregulation of oncogenes and upregulation of tumor suppressors and apoptosis. The therapeutic approach was validated by oral administration of 27 in orthotopic xenografts of endocrine-resistant breast cancer in monotherapy and in combination with fulvestrant. Importantly, at an equivalent dose in rats, thrombocytopenia was mitigated.
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U2 - 10.1021/acs.jmedchem.0c00456
DO - 10.1021/acs.jmedchem.0c00456
M3 - Article
C2 - 32453591
AN - SCOPUS:85088209623
SN - 0022-2623
VL - 63
SP - 7186
EP - 7210
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 13
ER -