ABSTRACT
Ubiquitination controls the stability of most cellular proteins, and its deregulation contributes to human diseases including cancer. Deubiquitinases remove ubiquitin from proteins, and their inhibition can induce the degradation of selected proteins, potentially including otherwise 'undruggable' targets. For example, the inhibition of ubiquitin-specific protease 7 (USP7) results in the degradation of the oncogenic E3 ligase MDM2, and leads to re-activation of the tumour suppressor p53 in various cancers. Here we report that two compounds, FT671 and FT827, inhibit USP7 with high affinity and specificity in vitro and within human cells. Co-crystal structures reveal that both compounds target a dynamic pocket near the catalytic centre of the auto-inhibited apo form of USP7, which differs from other USP deubiquitinases. Consistent with USP7 target engagement in cells, FT671 destabilizes USP7 substrates including MDM2, increases levels of p53, and results in the transcription of p53 target genes, induction of the tumour suppressor p21, and inhibition of tumour growth in mice.
Subject(s)
Piperidines/pharmacology , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Ubiquitin-Specific Peptidase 7/antagonists & inhibitors , Animals , Apoenzymes/antagonists & inhibitors , Apoenzymes/chemistry , Apoenzymes/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Crystallography, X-Ray , Female , Humans , Mice , Models, Molecular , Neoplasms/drug therapy , Neoplasms/enzymology , Neoplasms/pathology , Piperidines/chemical synthesis , Proto-Oncogene Proteins c-mdm2/chemistry , Proto-Oncogene Proteins c-mdm2/metabolism , Pyrazoles/chemical synthesis , Pyrimidines/chemical synthesis , Substrate Specificity , Transcription, Genetic/drug effects , Tumor Suppressor Protein p53/metabolism , Ubiquitin-Specific Peptidase 7/chemistry , Ubiquitin-Specific Peptidase 7/metabolism , Ubiquitination/drug effects , Xenograft Model Antitumor AssaysABSTRACT
A protein structure-guided drug design approach was employed to develop small molecule inhibitors of the BET family of bromodomains that were distinct from the known (+)-JQ1 scaffold class. These efforts led to the identification of a series of substituted benzopiperazines with structural features that enable interactions with many of the affinity-driving regions of the bromodomain binding site. Lipophilic efficiency was a guiding principle in improving binding affinity alongside drug-like physicochemical properties that are commensurate with oral bioavailability. Derived from this series was tool compound FT001, which displayed potent biochemical and cellular activity, translating to excellent in vivo activity in a mouse xenograft model (MV-4-11).
ABSTRACT
Two strategies toward the total synthesis of maoecrystal V (1) culminating in the construction of core structures 2 and 3 are described.
Subject(s)
Diterpenes/chemical synthesis , Cell Line, Tumor , Crystallography, X-Ray , Diterpenes/chemistry , Diterpenes/toxicity , Drug Screening Assays, Antitumor , HeLa Cells , Humans , Isodon/chemistry , Molecular Conformation , Plants, Medicinal/chemistryABSTRACT
In this paper, we describe the development of a novel series of high affinity, orally bioavailable 3-amino-1,4 benzodiazepine-based gamma-secretase inhibitors for the potential treatment of Alzheimer's disease. We disclose structure-activity relationships based around the 1, 3 and 5 positions of the benzodiazepine core structure.
Subject(s)
Alzheimer Disease/drug therapy , Benzodiazepines/chemical synthesis , Benzodiazepines/pharmacokinetics , Endopeptidases/metabolism , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Administration, Oral , Amines/chemical synthesis , Amines/pharmacokinetics , Amyloid Precursor Protein Secretases , Aspartic Acid Endopeptidases , Benzodiazepines/administration & dosage , Benzodiazepines/pharmacology , Biological Availability , Biotransformation , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/pharmacology , Humans , Molecular Structure , Structure-Activity RelationshipABSTRACT
A new approach to the synthesis of 1,4-benzodiazepines and 3-amino-1,4-benzodiazepines, which employs the Pd-catalyzed cross-coupling reaction of an imidoyl chloride with an organometallic reagent as the key step, is described. A five-step synthesis of a key intermediate is described and it is shown that in only four further steps (three couplings and a TFA-mediated BOC-deprotection) a wide variety of N1-, C3-amino-, C5-carbon-, or nitrogen-substituted 1,4-benzodiazepines can be synthesized.