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3 results on '"Rabow AA"'

1. Potent and selective bivalent inhibitors of BET bromodomains.

Author

Waring MJ, Chen H, Rabow AA, Walker G, Bobby R, Boiko S, Bradbury RH, Callis R, Clark E, Dale I, Daniels DL, Dulak A, Flavell L, Holdgate G, Jowitt TA, Kikhney A, McAlister M, Méndez J, Ogg D, Patel J, Petteruti P, Robb GR, Robers MB, Saif S, Stratton N, Svergun DI, Wang W, Whittaker D, Wilson DM, and Yao Y

Subjects
Apoptosis drug effects, Cell Cycle Proteins, Cell Line, Tumor, Cell Proliferation drug effects, Crystallography, X-Ray, Dose-Response Relationship, Drug, Humans, Ligands, Models, Molecular, Molecular Structure, Nuclear Proteins metabolism, Small Molecule Libraries chemistry, Structure-Activity Relationship, Substrate Specificity, Transcription Factors metabolism, Nuclear Proteins antagonists & inhibitors, Nuclear Proteins chemistry, Protein Domains drug effects, Small Molecule Libraries pharmacology, Transcription Factors antagonists & inhibitors, Transcription Factors chemistry
Abstract

Proteins of the bromodomain and extraterminal (BET) family, in particular bromodomain-containing protein 4 (BRD4), are of great interest as biological targets. BET proteins contain two separate bromodomains, and existing inhibitors bind to them monovalently. Here we describe the discovery and characterization of probe compound biBET, capable of engaging both bromodomains simultaneously in a bivalent, in cis binding mode. The evidence provided here was obtained in a variety of biophysical and cellular experiments. The bivalent binding results in very high cellular potency for BRD4 binding and pharmacological responses such as disruption of BRD4-mediator complex subunit 1 foci with an EC 50 of 100 pM. These compounds will be of considerable utility as BET/BRD4 chemical probes. This work illustrates a novel concept in ligand design-simultaneous targeting of two separate domains with a drug-like small molecule-providing precedent for a potentially more effective paradigm for developing ligands for other multi-domain proteins.

Published
2016
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2. AZD5153: A Novel Bivalent BET Bromodomain Inhibitor Highly Active against Hematologic Malignancies.

Author

Rhyasen GW, Hattersley MM, Yao Y, Dulak A, Wang W, Petteruti P, Dale IL, Boiko S, Cheung T, Zhang J, Wen S, Castriotta L, Lawson D, Collins M, Bao L, Ahdesmaki MJ, Walker G, O'Connor G, Yeh TC, Rabow AA, Dry JR, Reimer C, Lyne P, Mills GB, Fawell SE, Waring MJ, Zinda M, Clark E, and Chen H

Subjects
Animals, Antineoplastic Agents chemistry, Apoptosis drug effects, Biomarkers, Cell Cycle Proteins, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Disease Models, Animal, Dose-Response Relationship, Drug, E2F Transcription Factors genetics, E2F Transcription Factors metabolism, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic drug effects, Hematologic Neoplasms drug therapy, Hematologic Neoplasms genetics, Hematologic Neoplasms pathology, Humans, Mice, Molecular Targeted Therapy, Nuclear Proteins chemistry, Protein Binding, Proto-Oncogene Proteins c-myc genetics, Proto-Oncogene Proteins c-myc metabolism, Signal Transduction drug effects, TOR Serine-Threonine Kinases genetics, TOR Serine-Threonine Kinases metabolism, Transcription Factors chemistry, Tumor Burden drug effects, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Hematologic Neoplasms metabolism, Nuclear Proteins antagonists & inhibitors, Nuclear Proteins metabolism, Transcription Factors antagonists & inhibitors, Transcription Factors metabolism
Abstract

The bromodomain and extraterminal (BET) protein BRD4 regulates gene expression via recruitment of transcriptional regulatory complexes to acetylated chromatin. Pharmacological targeting of BRD4 bromodomains by small molecule inhibitors has proven to be an effective means to disrupt aberrant transcriptional programs critical for tumor growth and/or survival. Herein, we report AZD5153, a potent, selective, and orally available BET/BRD4 bromodomain inhibitor possessing a bivalent binding mode. Unlike previously described monovalent inhibitors, AZD5153 ligates two bromodomains in BRD4 simultaneously. The enhanced avidity afforded through bivalent binding translates into increased cellular and antitumor activity in preclinical hematologic tumor models. In vivo administration of AZD5153 led to tumor stasis or regression in multiple xenograft models of acute myeloid leukemia, multiple myeloma, and diffuse large B-cell lymphoma. The relationship between AZD5153 exposure and efficacy suggests that prolonged BRD4 target coverage is a primary efficacy driver. AZD5153 treatment markedly affects transcriptional programs of MYC, E2F, and mTOR. Of note, mTOR pathway modulation is associated with cell line sensitivity to AZD5153. Transcriptional modulation of MYC and HEXIM1 was confirmed in AZD5153-treated human whole blood, thus supporting their use as clinical pharmacodynamic biomarkers. This study establishes AZD5153 as a highly potent, orally available BET/BRD4 inhibitor and provides a rationale for clinical development in hematologic malignancies. Mol Cancer Ther; 15(11); 2563-74. ©2016 AACR., (©2016 American Association for Cancer Research.)

Published
2016
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3. Optimization of a Series of Bivalent Triazolopyridazine Based Bromodomain and Extraterminal Inhibitors: The Discovery of (3R)-4-[2-[4-[1-(3-Methoxy-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-4-piperidyl]phenoxy]ethyl]-1,3-dimethyl-piperazin-2-one (AZD5153).

Author

Bradbury RH, Callis R, Carr GR, Chen H, Clark E, Feron L, Glossop S, Graham MA, Hattersley M, Jones C, Lamont SG, Ouvry G, Patel A, Patel J, Rabow AA, Roberts CA, Stokes S, Stratton N, Walker GE, Ward L, Whalley D, Whittaker D, Wrigley G, and Waring MJ

Subjects
Animals, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents pharmacology, Caco-2 Cells, Cell Cycle Proteins, Crystallography, X-Ray, Dogs, Female, Hepatocytes drug effects, Hepatocytes metabolism, Heterocyclic Compounds, 2-Ring pharmacokinetics, Heterocyclic Compounds, 2-Ring pharmacology, Heterografts, Humans, Mice, SCID, Neoplasm Transplantation, Piperazines pharmacokinetics, Piperazines pharmacology, Protein Conformation, Pyrazoles, Pyridazines, Rats, Stereoisomerism, Structure-Activity Relationship, Antineoplastic Agents chemistry, Heterocyclic Compounds, 2-Ring chemistry, Nuclear Proteins antagonists & inhibitors, Piperazines chemistry, Transcription Factors antagonists & inhibitors
Abstract

Here we report the discovery and optimization of a series of bivalent bromodomain and extraterminal inhibitors. Starting with the observation of BRD4 activity of compounds from a previous program, the compounds were optimized for BRD4 potency and physical properties. The optimized compound from this campaign exhibited excellent pharmacokinetic profile and exhibited high potency in vitro and in vivo effecting c-Myc downregulation and tumor growth inhibition in xenograft studies. This compound was selected as the development candidate, AZD5153. The series showed enhanced potency as a result of bivalent binding and a clear correlation between BRD4 activity and cellular potency.

Published
2016
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