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

  • J Med Chem. 2020 Jul 9;63(13):7186-7210. doi: 10.1021/acs.jmedchem.0c00456.
Yangfeng Li  1 ,  Jiong Zhao  2 ,  Lauren M Gutgesell  2 ,  Zhengnan Shen  1 ,  Kiira Ratia  1  2  3 ,  Katherine Dye  1 ,  Oleksii Dubrovskyi  1 ,  Huiping Zhao  2 ,  Fei Huang  1 ,  Debra A Tonetti  2 ,  Gregory R J Thatcher  1  2 ,  Rui Xiong  1  2
Affiliations
  • 1. UICentre (Drug Discovery @ UIC), University of Illinois at Chicago, 833 S. Wood Street, Chicago, Illinois 60612, United States.
  • 2. Department of Pharmaceutical Sciences, University of Illinois College of Pharmacy, University of Illinois at Chicago, 833 S. Wood Street, Chicago, Illinois 60612, United States.
  • 3. Research Resources Center, University of Illinois at Chicago, Chicago, Illinois 60612, United States.
PMID: 32453591 DOI: 10.1021/acs.jmedchem.0c00456
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.

Products