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| Status |
Public on Jan 31, 2021 |
| Title |
Selective inhibition of the second bromodomain of BET family proteins results in robust antitumor activity in preclinical models of acute myeloid leukemia |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Dual bromodomain BET inhibitors (DbBi) that bind with similar affinities to the first and second bromodomains across BRD2, BRD3, BRD4 and BRDt only displayed modest activity as monotherapy in clinical trials. Thrombocytopenia, closely followed by symptoms characteristic of GI toxicity, have presented as dose limiting adverse events that may prevented escalation to higher dose levels for more robust efficacy. ABBV-744 is a highly selective inhibitor for the second bromodomain (BD2) of the four BET family proteins. In contrast to the broad antiproliferative activities observed with DbBi, ABBV-744 displayed significant antiproliferative activities largely but not exclusively in cancer cell lines derived from AML and androgen receptor (AR) positive prostate cancer. Studies in AML xenograft models demonstrated anti-tumor efficacy for ABBV-744 that was comparable to the pan-BET inhibitor ABBV-075 but with improved tolerability. Enhanced anti-tumor efficacy was also observed with the combination of ABBV-744 and the Bcl-2 inhibitor, venetoclax (ABT-199) compared to monotherapies of either agent alone. These results collectively support the clinical evaluation of ABBV-744 in AML (Clinical Trials.gov identifier: NCT03360006).
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| Overall design |
mRNA profiles of AML and NSCLC cell lines treated with ABBV-075, ABBV-744 or DMSO control, for 24 hours, using Illumina HiSeq3000.
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| Contributor(s) |
Lu X, Zhang L, Cai T, Lin X |
| Citation missing |
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| Submission date |
Jan 27, 2020 |
| Last update date |
Jan 31, 2021 |
| Contact name |
Xin Lu |
| E-mail(s) |
xin.x.lu@abbvie.com
|
| Phone |
847-937-7942
|
| Organization name |
Abbvie
|
| Department |
Oncology Discovery
|
| Street address |
1 North Waukegan Rd
|
| City |
North Chicago |
| State/province |
IL |
| ZIP/Postal code |
60064 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL21290 |
Illumina HiSeq 3000 (Homo sapiens) |
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| Samples (24)
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| Relations |
| BioProject |
PRJNA603369 |
| SRA |
SRP245430 |
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