Therapeutic impact of BET inhibitor BI 894999 treatment: backtranslation from the clinic

Abstract

Background BET inhibitors have been tested in several clinical trials where, despite encouraging preclinical results, substantial clinical benefit in monotherapy remains limited. This work illustrates the translational challenges and reports new data around the novel BET inhibitor, BI 894999. At clinically achievable concentrations, mechanistic studies were carried out to study pathway modulation and rational drug combinations. Methods BRD-NUT fusions are oncogenic drivers in NUT carcinoma (NC). The effects of BI 894999 on proliferation, chromatin binding and pathway modulation were studied in NC in vitro. These studies were complemented by efficacy studies either as a single agent or in combination with the clinical p300/CBP inhibitor CCS1477. Results Based on the modelling of preclinical and clinical data, we proposed and implemented a new clinical scheduling regimen. This led to plasma levels sufficient to fully dislodge BRD-NUT from chromatin and to sustained and pronounced pharmacodynamic (PD) modulation of HEXIM1 and HIST2H2BF. Platelet counts in patient blood samples were improved compared to previous schedules. Rational combination studies of BI 894999 performed at clinically meaningful concentrations led to tumour regressions in all NC xenograft models tested. Conclusions BI 894999 holds significant potential as a combination drug and CCS1477 p300/CBP inhibitor is a promising partner for future clinical trials.

Regulation of Cell Plasticity by Bromodomain and Extraterminal Domain (BET) Proteins: A New Perspective in Glioblastoma Therapy

“…BET bromodomain inhibitors (iBETs) are successfully employed in the treatment of inflammatory, metabolic, and cardiac disorders, as well as in cancer therapy [ 12 , 112 , 113 , 114 , 115 ]. Since their first identification almost a decade ago, iBETs have attracted considerable interest as anti-tumoral agents, due to their ability to induce an efficient downregulation of c-Myc expression [ 114 , 116 , 117 , 118 ].…”

Role of HOXA9 in solid tumors: mechanistic insights and therapeutic potential

“…Bardini et al reported that another BET inhibitor I-BET151 blocked the growth of MLL-AF4+ leukemic cells through affecting the transcription level of BRD4, HOXA7/HOXA9, and RUNX1 [ 150 ]. At present, fourteen BET inhibitors including AZD5153 [ 151 ], BMS-986158 [ 152 ], BI894999 [ 153 ], GS-5829 [ 154 ], GSK525762 [ 155 ], ABBV-075 [ 156 ], CPI-0610 [ 157 ], INCB057643 [ 158 ], OTX-015 [ 159 ], PLX51107 [ 160 ], INCB054329 [ 161 ], FT-1101 [ 162 ], CC-90010 [ 163 ], and ODM-207 [ 164 ] have been entered in the clinical testing.…”

Targeted Protein Degradation: Clinical Advances in the Field of Oncology

“…The catalytic role of BRD proteins in transcription led to the development of small-molecule inhibitors against BRDs. JQ1, the first BRD inhibitor reported [ 172 ], marks a success story of BRD4 as a novel therapeutic vulnerability, and paved the way for several BRD inhibitors with some being under clinical evaluation [ 171 , 173 , 174 , 175 , 176 , 177 , 178 , 179 ]. However, early phase clinical trials show only modest clinical activity as single agents in patients with advanced cancer [ 171 , 179 ].…”

“…JQ1, the first BRD inhibitor reported [ 172 ], marks a success story of BRD4 as a novel therapeutic vulnerability, and paved the way for several BRD inhibitors with some being under clinical evaluation [ 171 , 173 , 174 , 175 , 176 , 177 , 178 , 179 ]. However, early phase clinical trials show only modest clinical activity as single agents in patients with advanced cancer [ 171 , 179 ]. This can be explained by the assumption that small molecule BRD inhibitors may only block their chromatin binding function but spare other functional domains [ 171 ].…”