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

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.