Abstract LB-92: RVX-2135 is a novel, orally bioavailable epigenetic BET inhibitor that synergizes with cytarabine and idarubicin to inhibit proliferation of acute myeloid leukemia cells.
Bibliographic record
Abstract
Abstract Current treatment of acute myeloid leukemia (AML) often includes a combination of intravenous cytarabine (Ara-C) and an anthracycline such as idarubicin. Bromodomain and extra-terminal domain (BET) proteins contain two bromodomains that bind to acetylated lysines in histones and regulate gene transcription by an epigenetic mechanism. Here we describe a novel small molecule BET inhibitor, RVX-2135, which selectively binds recombinant BET bromodomains of BRD2, BRD3, and BRD4 but not non-BET bromodomains. RVX-2135 inhibited BRD2, BRD3, and BRD4 dual bromodomains binding to acetylated histones in vitro with sub to low micromolar IC50 values. In the human AML cell line MV4-11, RVX-2135 displaced BET proteins from chromatin and significantly reduced expression of c-MYC and BCL-2 mRNAs, with IC50s of 4 and 5 μM, respectively. RVX-2135 inhibited proliferation of cultured MV4-11 cells with an IC50 value of 6 μM, and induced cell cycle arrest and apoptosis. In vivo, nude mice bearing MV4-11 xenografts were treated orally with RVX-2135 at doses of 75 and 120 mg/kg b.i.d, and showed tumor growth inhibition of 77 and 92% respectively. There was a corresponding inhibition of c-MYC and BCL-2 mRNA expression in the xenograft tumors. In combination therapy in vitro, RVX-2135 synergized with idarubicin and cytarabine, with Chou-Talalay's combination indices of 0.17 and 0.18, respectively. The synergistic effect also translated into increased apoptosis when cytarabine was combined with RVX-2135. Similar data were seen with BET inhibitors from different chemical scaffolds, suggesting that this may represent a promising new class of drugs for AML. Citation Format: Eric Campeau, Ravi Jahagirdar, Jin Wu, Emily M. Gesner, Olesya Kharenko, Raymond Yu, Sarah Attwell, Henrik C. Hansen, Gregory S. Wagner, Kevin G. McLure, Peter R. Young. RVX-2135 is a novel, orally bioavailable epigenetic BET inhibitor that synergizes with cytarabine and idarubicin to inhibit proliferation of acute myeloid leukemia cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-92. doi:10.1158/1538-7445.AM2013-LB-92
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".