jq1-compound and Leukemia

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

Topics: Animals; Antineoplastic Agents; Cell Cycle Proteins; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Female; Humans; Indoles; Leukemia; Mice, SCID; Nuclear Proteins; Protein Serine-Threonine Kinases; Proteolysis; Pyrimidines; RNA-Binding Proteins; Small Molecule Libraries; Structure-Activity Relationship; Transcription Factors; Xenograft Model Antitumor Assays

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

Cellular signaling is often propagated by multivalent interactions. Multivalency creates avidity, allowing stable biophysical recognition. Multivalency is an attractive strategy for achieving potent binding to protein targets, as the affinity of bivalent ligands is often greater than the sum of monovalent affinities. The bromodomain and extraterminal domain (BET) family of transcriptional coactivators features tandem bromodomains through which BET proteins bind acetylated histones and transcription factors. All reported antagonists of the BET protein BRD4 bind in a monovalent fashion. Here we describe, to our knowledge for the first time, a bivalent BET bromodomain inhibitor-MT1-which has unprecedented potency. Biophysical and biochemical studies suggest MT1 is an intramolecular bivalent BRD4 binder that is more than 100-fold more potent, in cellular assays, than the corresponding monovalent antagonist, JQ1. MT1 significantly (P < 0.05) delayed leukemia progression in mice, as compared to JQ1. These data qualify a powerful chemical probe for BET bromodomains and a rationale for further development of multidomain inhibitors of epigenetic reader proteins.

Topics: Animals; Antineoplastic Agents; Apoptosis; Azepines; Cell Cycle Proteins; Cell Proliferation; Crystallography, X-Ray; Dose-Response Relationship, Drug; Drug Design; Humans; Leukemia; Ligands; Mice; Models, Molecular; Molecular Structure; Neoplasms, Experimental; Nuclear Proteins; Small Molecule Libraries; Structure-Activity Relationship; Transcription Factors; Triazoles

Small-molecule inhibitors of bromodomain and extra terminal proteins (BET), including BRD2, BRD3, and BRD4 proteins have therapeutic potential for the treatment of human cancers and other diseases and conditions. In this paper, we report the design, synthesis, and evaluation of γ-carboline-containing compounds as a new class of small-molecule BET inhibitors. The most potent inhibitor (compound 18, RX-37) obtained from this study binds to BET bromodomain proteins (BRD2, BRD3, and BRD4) with Ki values of 3.2-24.7 nM and demonstrates high selectivity over other non-BET bromodomain-containing proteins. Compound 18 potently and selectively inhibits cell growth in human acute leukemia cell lines harboring the rearranged mixed lineage leukemia 1 gene. We have determined a cocrystal structure of 18 in complex with BRD4 BD2 at 1.4 Å resolution, which provides a solid structural basis for the compound's high binding affinity and for its further structure-based optimization. Compound 18 represents a promising lead compound for the development of a new class of therapeutics for the treatment of human cancer and other conditions.

Topics: Antineoplastic Agents; Carbolines; Cell Cycle Proteins; Cell Line, Tumor; Crystallography, X-Ray; Humans; Leukemia; Molecular Docking Simulation; Nuclear Proteins; Protein Serine-Threonine Kinases; RNA-Binding Proteins; Transcription Factors