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

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.

XP-524 is a dual-BET/EP300 inhibitor that represses oncogenic KRAS and potentiates immune checkpoint inhibition in pancreatic cancer

“…Hence, while the substantial efficacy of XP-524 is encouraging, translating these findings to the clinic will require careful evaluation of any potential adverse effects. While our previous observations suggest that XP-524 does reduce platelets in the rat model of thrombocytopenia, the risk of other off-target effects cannot be ignored ( 23 ).…”

“…Given the conserved expression patterns of BRD4 and EP300/CBP in PDAC tissues, we next explored the potential of the novel compound XP-524 ( 23 ) as a dual-specificity inhibitor targeting the bromodomains of BRD4 and EP300/CBP ( Fig. 2 A ).…”

“…XP-524 was designed and synthesized as described previously ( 23 ). JQ-1 and SGC-CBP30 were purchased from Sigma-Aldrich and reconstituted in sterile PBS at a stock concentration of 10 μM immediately before use.…”

“…To address this, our group has recently synthesized the compound XP-524 ( 23 ), designed to simultaneously target the bromodomains of BRD4 and EP300/CBP. After verifying the selectivity and potency of this compound, we conducted several in vitro studies affirming that XP-524 has improved efficacy compared to the benchmark BET inhibitor JQ-1 and comparable efficacy to high-dose JQ-1 combined with EP300/CBP inhibition.…”

Discovery of novel 4-phenylquinazoline-based BRD4 inhibitors for cardiac fibrosis

“…BD1 is mainly regarded as a chromatin-binding module and BD2 is typically used for transcription factor recruitment 4 , 5 . Among the BET family, BRD4 is extensively explored and associated with various pathologic states, such as cancers, inflammation and cardiovascular diseases 6 , 7 , 8 , 9 .…”