ABSTRACT
Transcriptional deregulation is a hallmark of many cancers and is exemplified by genomic amplifications of the MYC family of oncogenes, which occur in at least 20% of all solid tumors in adults. Targeting of transcriptional cofactors and the transcriptional cyclin-dependent kinase (CDK9) has emerged as a therapeutic strategy to interdict deregulated transcriptional activity including oncogenic MYC. Here, we report the structural optimization of a small molecule microarray hit, prioritizing maintenance of CDK9 selectivity while improving on-target potency and overall physicochemical and pharmacokinetic (PK) properties. This led to the discovery of the potent, selective, orally bioavailable CDK9 inhibitor 28 (KB-0742). Compound 28 exhibits in vivo antitumor activity in mouse xenograft models and a projected human PK profile anticipated to enable efficacious oral dosing. Notably, 28 is currently being investigated in a phase 1/2 dose escalation and expansion clinical trial in patients with relapsed or refractory solid tumors.
Subject(s)
Antineoplastic Agents , Neoplasms , Adult , Humans , Animals , Mice , Cyclin-Dependent Kinases , Cell Line, Tumor , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/chemistry , Apoptosis , Cell Cycle Checkpoints , Disease Models, Animal , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/chemistry , Cyclin-Dependent Kinase 9 , Neoplasms/drug therapyABSTRACT
Castration-resistant prostate cancers (CRPCs) lose sensitivity to androgen-deprivation therapies but frequently remain dependent on oncogenic transcription driven by the androgen receptor (AR) and its splice variants. To discover modulators of AR-variant activity, we used a lysate-based small-molecule microarray assay and identified KI-ARv-03 as an AR-variant complex binder that reduces AR-driven transcription and proliferation in prostate cancer cells. We deduced KI-ARv-03 to be a potent, selective inhibitor of CDK9, an important cofactor for AR, MYC, and other oncogenic transcription factors. Further optimization resulted in KB-0742, an orally bioavailable, selective CDK9 inhibitor with potent anti-tumor activity in CRPC models. In 22Rv1 cells, KB-0742 rapidly downregulates nascent transcription, preferentially depleting short half-life transcripts and AR-driven oncogenic programs. In vivo, oral administration of KB-0742 significantly reduced tumor growth in CRPC, supporting CDK9 inhibition as a promising therapeutic strategy to target AR dependence in CRPC.
Subject(s)
Androgen Receptor Antagonists/pharmacology , Cyclin-Dependent Kinase 9/antagonists & inhibitors , Prostatic Neoplasms, Castration-Resistant/drug therapy , Protein Kinase Inhibitors/pharmacology , Receptors, Androgen/genetics , Transcription, Genetic/drug effects , Androgen Receptor Antagonists/therapeutic use , Animals , Cell Line, Tumor , Cyclin-Dependent Kinase 9/genetics , Gene Expression Regulation, Neoplastic/drug effects , Male , Mice , Mice, Inbred BALB C , Models, Molecular , Prostatic Neoplasms, Castration-Resistant/genetics , Protein Kinase Inhibitors/therapeutic useABSTRACT
The first Pd-catalyzed arylation of aza-Achmatowicz rearrangement products with arylboronic acids is achieved, providing versatile 2-aryldihydropyridinones for facile synthesis of highly functionalized 2-arylpiperidines. Key to this arylation is the use of non-phosphine-ligand palladium precatalyst. The substrate scope is demonstrated with >26 examples, and the utility of 2-aryldihydropyridinones is illustrated by the synthesis of a small collection of 2-arylpiperidines with substituents or functional groups at any carbon (C2-C6) as well as two NK1 receptor antagonists (+)-CP-999,94 and (+)-L-733,060.
ABSTRACT
In recent years, the first generation of ß-secretase (BACE1) inhibitors advanced into clinical development for the treatment of Alzheimer's disease (AD). However, the alignment of drug-like properties and selectivity remains a major challenge. Herein, we describe the discovery of a novel class of potent, low clearance, CNS penetrant BACE1 inhibitors represented by thioamidine 5. Further profiling suggested that a high fraction of the metabolism (>95%) was due to CYP2D6, increasing the potential risk for victim-based drug-drug interactions (DDI) and variable exposure in the clinic due to the polymorphic nature of this enzyme. To guide future design, we solved crystal structures of CYP2D6 complexes with substrate 5 and its corresponding metabolic product pyrazole 6, which provided insight into the binding mode and movements between substrate/inhibitor complexes. Guided by the BACE1 and CYP2D6 crystal structures, we designed and synthesized analogues with reduced risk for DDI, central efficacy, and improved hERG therapeutic margins.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Amyloid Precursor Protein Secretases/chemistry , Aspartic Acid Endopeptidases/antagonists & inhibitors , Aspartic Acid Endopeptidases/chemistry , Cytochrome P-450 CYP2D6/chemistry , Drug Interactions , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Amino Acid Sequence , Amyloidogenic Proteins/metabolism , Animals , Crystallography, X-Ray , Cytochrome P-450 CYP2D6/genetics , Cytochrome P-450 CYP2D6/metabolism , Drug Design , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Ether-A-Go-Go Potassium Channels/metabolism , Humans , Inhibitory Concentration 50 , Male , Mice, Inbred Strains , Models, Molecular , Molecular Sequence Data , Protease Inhibitors/administration & dosage , Protease Inhibitors/pharmacokinetics , Pyrazoles/chemistry , Structure-Activity RelationshipABSTRACT
We report a fundamentally unique approach to the catalytic kinetic resolution of amine derivatives based on formamide and thioformamide substrates. Readily accessible histidine-containing peptides mediate the kinetic resolutions with as little as 5 mol % catalyst. Selectivity factors (k(rel)) as high as 43.7 were observed under simple reaction conditions utilizing Boc(2)O as the reagent at room temperature. Mechanistic experiments were conducted that established a higher level of reactivity for thioformamide substrates than for their formamide analogues. The products of these asymmetric reactions were shown to be readily converted to desirable building blocks such as N-Boc-amines and the parent chiral formamide compounds.
Subject(s)
Amines/chemistry , Carbonates/chemistry , Peptides/chemistry , Carbonates/chemical synthesis , Catalysis , KineticsABSTRACT
HIV protease inhibitors (HIV PI) are a class of antiretroviral drugs that are designed to target the viral protease. Unexpectedly, this class of drugs is also reported to have antitumor activity. In this study, we have evaluated the in vitro activity of nelfinavir, a HIV PI, against human melanoma cells. Nelfinavir inhibits the growth of melanoma cell lines at low micromolar concentrations that are clinically attainable. Nelfinavir promotes apoptosis and arrests cell cycle at G(1) phase. Cell cycle arrest is attributed to inhibition of cyclin-dependent kinase 2 (CDK2) and concomitant dephosphorylation of retinoblastoma tumor suppressor. We further show that nelfinavir inhibits CDK2 through proteasome-dependent degradation of Cdc25A phosphatase. Our results suggest that nelfinavir is a promising candidate chemotherapeutic agent for advanced melanoma, for which novel and effective therapies are urgently needed.
Subject(s)
Melanoma/drug therapy , Melanoma/pathology , Nelfinavir/pharmacology , Apoptosis/drug effects , Cell Growth Processes/drug effects , Cell Line, Tumor , Colonic Neoplasms/drug therapy , Colonic Neoplasms/pathology , Cyclin-Dependent Kinase 2/antagonists & inhibitors , Cyclin-Dependent Kinase 2/metabolism , G1 Phase/drug effects , HIV Protease Inhibitors/pharmacology , Humans , Melanoma/enzymology , Melanoma/metabolism , Phosphorylation/drug effects , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Proto-Oncogene Proteins c-akt/metabolism , Retinoblastoma Protein/metabolism , Signal Transduction/drug effects , cdc25 Phosphatases/metabolismABSTRACT
[reaction: see text] A new method for the synthesis of substituted pyranone hemiketals from dioxanorbornanes via SmI(2) is described. Also reported is a synthesis of spiro[4.5]ketals from analogous intermediates via acid-promoted deprotection/ketalization.
