rvx-208 and Leukemia

Bromodomain-containing protein 4 (BRD4), an epigenetic reader of acetyl lysine, has emerged as a promising therapeutic target for many diseases including cancer, inflammation and heart failure. Our previous study reported that nitroxoline, an FDA approved antibiotic, showed potential BRD4 inhibitory activity and antiproliferation activity against leukemia cell lines. In this study, we further explored the structure-activity relationship (SAR) around nitroxoline and employed our previously developed machine learning based activity scoring function BRD4LGR for further analysis. To improve the cellular level activity, physico-chemical properties were optimized using computational approaches. Then the candidates were tested for their ADME/T profiles. Finally, based on this rational hit-to-lead optimization strategy, 3 drug-like BRD4 inhibitors were obtained, with different profiles on cell line selectivity for multiple myeloma, leukemia and triple negative breast cancer. Further mechanism study showed these compounds could down-regulate c-Myc to inhibit cancer cell growth. This work illustrates the application of multiple computer-aided drug design techniques in a hit-to-lead optimization scenario, and provides novel potent BRD4 inhibitors with different phenotype propensities for future cancer treatment.

Topics: Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Computer-Aided Design; Drug Design; Humans; Imidazoles; Leukemia; Multiple Myeloma; Nitroquinolines; Nuclear Proteins; Proto-Oncogene Proteins c-myc; Quinolines; Structure-Activity Relationship; Transcription Factors; Triple Negative Breast Neoplasms

Topics: Antineoplastic Agents; Cell Cycle; Cell Cycle Proteins; Drug Design; Humans; Isoxazoles; Leukemia; Proto-Oncogene Proteins c-myc; Pyridones; Transcription Factors; Tumor Cells, Cultured

The discovery of inhibitors of bromodomain and extra terminal domain (BET) has achieved great progress, and at least seven inhibitors have progressed into clinical trials for the treatment of cancer or inflammatory diseases. Here, we describe the identification, optimization, and evaluation of benzo[cd]indol-2(1H)-one containing compounds as a new class of BET bromodomain inhibitors, starting from structure-based virtual screening (SBVS). Through structure-based optimization, potent compounds were obtained with significantly improved activity. The two most potent compounds bind to the BRD4 bromodomain, with Kd values of 124 and 137 nM. Selected compounds exhibited high selectivity over other non-BET subfamily members. Notably, compound 85 demonstrated a reasonable antiproliferation effect on MV4;11 leukemia cells and exhibited a good pharmacokinetic profile with high oral bioavailability (75.8%) and moderate half-life (T1/2 = 3.95 h). The resulting lead molecule 85 represents a new, potent, and selective class of BET bromodomain inhibitors for the development of therapeutics to treat cancer and inflammatory diseases.

Topics: Animals; Antineoplastic Agents; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Crystallography, X-Ray; Drug Discovery; Humans; Indoles; Leukemia; Molecular Docking Simulation; Nuclear Proteins; Rats; Structure-Activity Relationship; Transcription Factors

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Azepines; Benzodiazepines; Cell Cycle Proteins; Cell Proliferation; Gene Expression; Humans; Leukemia; Nuclear Proteins; Protein Serine-Threonine Kinases; Quinazolines; Quinazolinones; RNA-Binding Proteins; Transcription Factors; Triazoles