ABSTRACT
Recent studies suggest that targeting transcriptional machinery can lead to potent and selective anticancer effects in cancers dependent on high and constant expression of certain transcription factors for growth and survival. Cyclin-dependent kinase 7 (CDK7) is the catalytic subunit of the CDK-activating kinase complex. Its function is required for both cell-cycle regulation and transcriptional control of gene expression. CDK7 has recently emerged as an attractive cancer target because its inhibition leads to decreased transcript levels of oncogenic transcription factors, especially those associated with super-enhancers. Here, we describe a selective CDK7 inhibitor SY-1365, which is currently in clinical trials in populations of patients with ovarian and breast cancer (NCT03134638). In vitro, SY-1365 inhibited cell growth of many different cancer types at nanomolar concentrations. SY-1365 treatment decreased MCL1 protein levels, and cancer cells with low BCL2L1 (BCL-XL) expression were found to be more sensitive to SY-1365. Transcriptional changes in acute myeloid leukemia (AML) cell lines were distinct from those following treatment with other transcriptional inhibitors. SY-1365 demonstrated substantial antitumor effects in multiple AML xenograft models as a single agent; SY-1365-induced growth inhibition was enhanced in combination with the BCL2 inhibitor venetoclax. Antitumor activity was also observed in xenograft models of ovarian cancer, suggesting the potential for exploring SY-1365 in the clinic in both hematologic and solid tumors. Our findings support targeting CDK7 as a new approach for treating transcriptionally addicted cancers. SIGNIFICANCE: These findings demonstrate the molecular mechanism of action and potent antitumor activity of SY-1365, the first selective CDK7 inhibitor to enter clinical investigation.
Subject(s)
Apoptosis/drug effects , Cell Proliferation/drug effects , Cyclin-Dependent Kinases/antagonists & inhibitors , Ovarian Neoplasms/pathology , Protein Kinase Inhibitors/pharmacology , Animals , Cell Cycle/drug effects , Cyclin-Dependent Kinases/genetics , Cyclin-Dependent Kinases/metabolism , Female , High-Throughput Screening Assays , Humans , Mice , Mice, Inbred NOD , Mice, SCID , Models, Molecular , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/enzymology , Protein Kinase Inhibitors/chemistry , Tumor Cells, Cultured , Xenograft Model Antitumor Assays , Cyclin-Dependent Kinase-Activating KinaseABSTRACT
In contrast to studies on class I histone deacetylase (HDAC) inhibitors, the elucidation of the molecular mechanisms and therapeutic potential of class IIa HDACs (HDAC4, HDAC5, HDAC7 and HDAC9) is impaired by the lack of potent and selective chemical probes. Here we report the discovery of inhibitors that fill this void with an unprecedented metal-binding group, trifluoromethyloxadiazole (TFMO), which circumvents the selectivity and pharmacologic liabilities of hydroxamates. We confirm direct metal binding of the TFMO through crystallographic approaches and use chemoproteomics to demonstrate the superior selectivity of the TFMO series relative to a hydroxamate-substituted analog. We further apply these tool compounds to reveal gene regulation dependent on the catalytic active site of class IIa HDACs. The discovery of these inhibitors challenges the design process for targeting metalloenzymes through a chelating metal-binding group and suggests therapeutic potential for class IIa HDAC enzyme blockers distinct in mechanism and application compared to current HDAC inhibitors.
Subject(s)
Histone Deacetylase Inhibitors/chemistry , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylases/metabolism , Zinc/chemistry , Cell Line, Tumor , Crystallography, X-Ray , Dose-Response Relationship, Drug , Histone Deacetylase Inhibitors/chemical synthesis , Histone Deacetylases/genetics , Humans , Models, Molecular , Molecular Structure , Organometallic Compounds/chemical synthesis , Organometallic Compounds/chemistry , Organometallic Compounds/pharmacology , Oxadiazoles/chemistry , Structure-Activity Relationship , Zinc/metabolismABSTRACT
The first total synthesis of dolabelide D (or of any of the closely related dolabelides) has been achieved with a longest linear sequence of 17 steps. Key features of the synthesis include an application of the catalytic asymmetric silane alcoholysis, the tandem silylformylation-crotylsilylation, and a Brook-like 1,4-carbon to oxygen silyl migration.
Subject(s)
Diterpenes/chemical synthesis , Animals , Macrolides , Mollusca/chemistry , Silanes/chemistryABSTRACT
[structure: see text] A synthesis of the C(15)-C(30) fragment of Dolabelides A and B has been achieved. The recently developed asymmetric silane alcoholysis and tandem silylformylation-crotylsilylation reactions were used as the key steps to establish the C(23)-C(27) 1,5-syn-diol. In addition, the flexibility of this methodology has been demonstrated with an efficient synthesis of the C(24)-C(25) trisubstituted olefin.
Subject(s)
Antineoplastic Agents/chemical synthesis , Diterpenes/chemical synthesis , Alkenes/chemical synthesis , Antineoplastic Agents/pharmacology , Butanols/chemistry , Formates/chemistry , Ketones/chemical synthesis , Macrolides , Molecular Structure , Silanes/chemistry , StereoisomerismABSTRACT
A new asymmetric synthesis of chiral silanes has been developed. Chiral phosphine-modified copper complexes catalyze the alcoholysis of prochiral dihydrosilanes with good to excellent stereoselectivity at silicon. The application of this methodology to the tandem silylformylation-allylsilylation of alkynes has been demonstrated.