Novel Pyrrolopyridone Bromodomain and Extra-Terminal Motif (BET) Inhibitors Effective in Endocrine-Resistant ER+ Breast Cancer with Acquired Resistance to Fulvestrant and Palbociclib

Yangfeng Li, Jiong Zhao, Lauren M. Gutgesell, Zhengnan Shen, Kiira Ratia, Katherine Dye, Oleksii Dubrovskyi, Huiping Zhao, Fei Huang, Debra A. Tonetti, Gregory R.J. Thatcher, Rui Xiong

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)7186-7210
Number of pages25
JournalJournal of Medicinal Chemistry
Volume63
Issue number13
DOIs
StatePublished - Jul 9 2020
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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