ABSTRACT
Advanced basal cell carcinomas (BCCs) circumvent Smoothened (SMO) inhibition by activating GLI transcription factors to sustain the high levels of Hedgehog (HH) signaling required for their survival. Unfortunately, there is a lack of efficacious therapies. We performed a gene expression-based drug repositioning screen in silico and identified the FDA-approved histone deacetylase (HDAC) inhibitor, vorinostat, as a top therapeutic candidate. We show that vorinostat only inhibits proliferation of BCC cells in vitro and BCC allografts in vivo at high dose, limiting its usefulness as a monotherapy. We leveraged this in silico approach to identify drug combinations that increase the therapeutic window of vorinostat and identified atypical PKC Æ/Ê (aPKC) as a HDAC costimulator of HH signaling. We found that aPKC promotes GLI1-HDAC1 association in vitro, linking two positive feedback loops. Combination targeting of HDAC1 and aPKC robustly inhibited GLI1, lowering drug doses needed in vitro, in vivo, and ex vivo in patient-derived BCC explants. We identified a bioavailable and selective small-molecule aPKC inhibitor, bringing the pharmacological blockade of aPKC and HDAC1 into the realm of clinical possibility. Our findings provide a compelling rationale and candidate drugs for combined targeting of HDAC1 and aPKC in HH-dependent cancers.
Subject(s)
Carcinoma, Basal Cell/drug therapy , Histone Deacetylase 1/drug effects , Histone Deacetylase Inhibitors/pharmacology , Isoenzymes/drug effects , Protein Kinase C/drug effects , Skin Neoplasms/drug therapy , Allografts , Animals , Carcinoma, Basal Cell/genetics , Cell Line, Tumor , Cell Proliferation/drug effects , Computational Biology , Drug Combinations , Drug Discovery , Gene Expression Profiling , Gene Expression Regulation, Neoplastic/drug effects , Hedgehogs/genetics , Hedgehogs/metabolism , Histone Deacetylase 1/genetics , Histone Deacetylase 1/metabolism , Histone Deacetylase Inhibitors/chemistry , Isoenzymes/metabolism , Mice , Mice, Knockout , Protein Kinase C/metabolism , Signal Transduction , Transcription Factors/drug effects , Transcription Factors/genetics , Zinc Finger Protein GLI1/genetics , Zinc Finger Protein GLI1/metabolismABSTRACT
The spread of intra-abdominal cancers is a vexing clinical problem for which there is no widely effective treatment. We discovered previously that (2E)-3-[(4-tert-butylphenyl)sulfonyl]acrylonitrile (1) induced cancer cell apoptosis during adhesion to normal mesothelial cells which line the peritoneum. We recently demonstrated that the sulfonylacrylonitrile portion of 1 and hydrophobic aryl substitution were essential for pro-apoptotic activity in cancer cells. Here we synthesized a diverse series of analogues of 1 in order to improve the efficacy and pharmaceutical properties. Analogues and 1 were compared in their ability to cause cancer cell death during adhesion to normal mesothelial cell monolayers. Potent analogues identified in the in vitro assay were validated and found to exhibit improved inhibition of intra-abdominal cancer in two clinically relevant murine models of ovarian and pancreatic cancer spread and metastasis, highlighting their potential clinical use as an adjunct to surgical resection of cancers.
Subject(s)
Acrylonitrile/pharmacology , Antineoplastic Agents/pharmacology , Drug Design , Ovarian Neoplasms/drug therapy , Pancreatic Neoplasms/drug therapy , Sulfones/pharmacology , Acrylonitrile/chemical synthesis , Acrylonitrile/chemistry , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Female , HT29 Cells , Humans , Mice , Molecular Structure , Ovarian Neoplasms/pathology , Ovarian Neoplasms/secondary , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/secondary , Structure-Activity Relationship , Sulfones/chemical synthesis , Sulfones/chemistryABSTRACT
The vast majority of cancer patients die from metastasis, the process by which cancer cells spread to secondary tissues through body fluids. Peritoneal carcinomatosis is a type of metastasis in which cancer cells gain access to the intra-abdominal cavity and then implant in the peritoneum, the thin tissue that lines the abdominal wall and internal organs. Unfortunately, peritoneal carcinomatosis can occur following surgical resection of intra-abdominal malignancies. We previously reported proapoptotic activity of (2E)-3-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2-propenenitrile (BAY 11-7085, 1) on colon and pancreatic cancer cells during adhesion and demonstrated that this compound could significantly inhibit peritoneal carcinomatosis in mice.(1,2) In order to determine the chemical basis of the anti-metastatic properties of BAY 11-7085, a series of analogs were synthesized and evaluated for their ability to induce apoptosis in pancreatic and ovarian cancer cells during adhesion to mesothelial cells, which line the surface of the peritoneum. The co-culture assay results were validated using a murine peritoneal carcinomatosis model. These analogs may greatly benefit patients undergoing surgical resections of colorectal, pancreatic, and ovarian cancers depending on their tolerability.
Subject(s)
Acrylonitrile/chemistry , Acrylonitrile/therapeutic use , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Carcinoma/drug therapy , Peritoneal Neoplasms/drug therapy , Acrylonitrile/chemical synthesis , Animals , Antineoplastic Agents/chemical synthesis , Apoptosis/drug effects , Carcinoma/pathology , Carcinoma/secondary , Cell Line, Tumor , Coculture Techniques , Female , Humans , Mice , Nitriles/chemical synthesis , Nitriles/chemistry , Nitriles/therapeutic use , Ovarian Neoplasms/drug therapy , Ovary/drug effects , Ovary/pathology , Peritoneal Neoplasms/pathology , Peritoneal Neoplasms/secondary , Peritoneum/drug effects , Peritoneum/pathology , Sulfones/chemical synthesis , Sulfones/chemistry , Sulfones/therapeutic useABSTRACT
The elaboration of a novel scaffold for the inhibition of JAK2 and FAK kinases was targeted in order to provide a dual inhibitor that could target divergent pathways for tumor cell progression.
Subject(s)
Focal Adhesion Protein-Tyrosine Kinases/chemistry , Janus Kinase 2/chemistry , Protein Kinase Inhibitors/pharmacology , Animals , Cell Line, Tumor , Chemistry, Pharmaceutical/methods , Disease Progression , Drug Design , Humans , Inhibitory Concentration 50 , Mice , Models, Chemical , Mutation , Neoplasms/genetics , Neoplasms/pathology , Protein Kinase Inhibitors/chemical synthesis , Rats , Rats, Sprague-Dawley , Signal Transduction , Time FactorsABSTRACT
Chemical strategies to mitigate cytochrome P450-mediated bioactivation of novel 2,7-disubstituted pyrrolo[2,1-f][1,2,4]triazine ALK inhibitors are described along with synthesis and biological activity. Piperidine-derived analogues showing minimal microsomal reactive metabolite formation were discovered. Potent, selective, and metabolically stable ALK inhibitors from this class were identified, and an orally bioavailable compound (32) with antitumor efficacy in ALK-driven xenografts in mouse models was extensively characterized.
Subject(s)
Aniline Compounds/chemical synthesis , Antineoplastic Agents/chemical synthesis , Pyrroles/chemical synthesis , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Triazines/chemical synthesis , Administration, Oral , Anaplastic Lymphoma Kinase , Aniline Compounds/pharmacokinetics , Aniline Compounds/pharmacology , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Biological Availability , In Vitro Techniques , Mice , Mice, SCID , Microsomes, Liver/metabolism , Pyrroles/pharmacokinetics , Pyrroles/pharmacology , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Triazines/pharmacokinetics , Triazines/pharmacology , Xenograft Model Antitumor AssaysABSTRACT
The incorporation of R,R-1,2-diaminocyclohexane at C4 in a series of 2,4-diaminopyrimidines led to a number of ALK inhibitors in which optimized activity was achieved by conversion of the 2-amino group into a methanesulfonamide. Tumor growth inhibition was observed when an orally bioavailable analog was evaluated in a Karpas-299 tumor xenograft mouse model.
Subject(s)
Antineoplastic Agents/chemical synthesis , Cyclohexylamines/chemical synthesis , Pyrimidines/chemical synthesis , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Administration, Oral , Anaplastic Lymphoma Kinase , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacology , Cyclohexylamines/administration & dosage , Cyclohexylamines/pharmacology , Enzyme Activation/drug effects , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Infusion Pumps , Inhibitory Concentration 50 , Mice , Molecular Structure , Neoplasms/drug therapy , Pyrimidines/administration & dosage , Pyrimidines/pharmacology , Rats , Rats, Sprague-Dawley , Xenograft Model Antitumor AssaysABSTRACT
Elaboration of the SAR around a series of 2,4-diaminopyrimidines led to a number of c-Met inhibitors in which kinase selectivity was modulated by substituents appended on the C4-aminobenzamide ring and the nature of the C2-aminoaryl ring. Further lead optimization of the C2-aminoaryl group led to benzoxazepine analogs whose pharmaceutical properties were modulated by the nature of the substituent on the benzoxazepine nitrogen. Tumor stasis (with partial regressions) were observed when an orally bioavailable analog was evaluated in a GTL-16 tumor xenograft mouse model. Subsequent PK/PD studies suggested that a metabolite contributed to the overall in vivo response.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Neoplasms/drug therapy , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Pyrimidines/chemistry , Pyrimidines/therapeutic use , Administration, Oral , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Humans , Mice , Mice, Nude , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-met/metabolism , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Xenograft Model Antitumor AssaysABSTRACT
The HGF-c-Met signaling axis is an important paracrine mediator of epithelial-mesenchymal cell interactions involving the regulation of multiple cellular activities including cell motility, mitogenesis, morphogenesis, and angiogenesis. Dysregulation of c-Met signaling (e.g., overexpression or increased activation) is associated with the development of a wide range of tumor types; thus, inhibiting the HGF-c-Met pathway is predicted to lead to anti-tumor effects in many cancers. Elaboration of a 2-arylaminopyrimidine scaffold led to a series of potent c-Met inhibitors bearing a C4-2-amino-N-methylbenzamide group. Specifically, a series of C2-benzazepinone analogs demonstrated potent inhibition of c-Met in enzymatic and cellular assays. Kinase selectivity could be tuned by varying the nature of the alkyl group on the benzazepinone nitrogen.
Subject(s)
Bridged Bicyclo Compounds/chemistry , Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Pyrimidines/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Bridged Bicyclo Compounds/chemical synthesis , Bridged Bicyclo Compounds/pharmacology , Cell Line, Tumor , Humans , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-met/metabolism , Structure-Activity RelationshipABSTRACT
Dysregulation of the anaplastic lymphoma kinase (ALK) is implicated in a variety of cancers. A series of tetrahydropyrido[2,3-b]pyrazines was constructed as ring-constrained analogs of a known aminopyridine kinase scaffold. Chemistry was developed to rapidly elaborate the SAR, structural elements impacting ALK inhibitory activity were exploited, and kinase selective analogs were identified that inhibit ALK with IC(50) values approximately 10 nM (enzyme) and approximately 150 nM (cell).
Subject(s)
Antineoplastic Agents/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrazines/chemistry , Anaplastic Lymphoma Kinase , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Binding Sites , Computer Simulation , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/metabolism , Pyrazines/chemical synthesis , Pyrazines/pharmacology , Receptor Protein-Tyrosine Kinases , Structure-Activity RelationshipABSTRACT
A stereoselective halo-etherification of chiral enamides is described here. This work provides an approach to halogen containing cyclic ethers and reveals further mechanistic insights to the chemistry of chiral enamides.
Subject(s)
Ethers, Cyclic/chemical synthesis , Hydrocarbons, Halogenated/chemical synthesis , Models, Molecular , Molecular StructureABSTRACT
Thiazolium azomethine ylides, equipped with a C-2 methanethiol group, participate in an efficient [3 + 2] cycloaddition reaction with acetylene derivatives to yield unique pyrrolo[2,1-b]thiazoles. The elimination of the methanethiol leaving group from the cycloadduct has replaced the need for a separate oxidation step and suppresses ring-opening side reactions. Products were obtained in short synthetic sequences to demonstrate their use as a scaffold for compound libraries.
Subject(s)
Azo Compounds/chemistry , Pyrroles/chemical synthesis , Thiazoles/chemistry , Thiazoles/chemical synthesis , Thiosemicarbazones/chemistry , Alkynes/chemistry , Combinatorial Chemistry Techniques , Cyclization , Molecular Structure , Pyrroles/chemistryABSTRACT
Total syntheses of indoloquinolizidine alkaloid (+/-)-, R-(+)-, and S-(-)-deplancheine are described here. The synthesis features an enantioselective intramolecular formal aza-[3 + 3] cycloaddition for the construction of the quinolizidine CD-ring. This application serves to introduce a new synthetic strategy for the synthesis of indoloquinolizidine alkaloids.
Subject(s)
Indole Alkaloids/chemical synthesis , Indole Alkaloids/chemistry , Magnetic Resonance Spectroscopy , StereoisomerismABSTRACT
[reaction: see text] A 19-step stereoselective total synthesis of (+/-)-tangutorine is described here. The total synthesis features an intramolecular aza-[3 + 3] formal cycloaddition strategy and also a Heck coupling for constructing the C2-C3 bond. This work provides a novel approach toward the indoloquinolizidine family of alkaloids.
Subject(s)
Alkaloids/chemistry , Aza Compounds/chemistry , Carbolines/chemistry , Carbolines/chemical synthesis , Indolequinones/chemistry , Quinolizines/chemistry , Quinolizines/chemical synthesis , Molecular Structure , StereoisomerismABSTRACT
A highly stereoselective preparation of novel chiral (E)-alpha-haloenamides under mild conditions utilizing magnesium halide salts is described. This unexpected mild and efficient hydrohalogenation reaction highlights another synthetic utility of ynamides. [reaction: see text]
ABSTRACT
A detailed account regarding a formal [3 + 3] cycloaddition method using 4-hydroxy-2-pyrones and 1,3-diketones is described here. This formal cycloaddition reaction or annulation reaction is synthetically useful for constructing 2H-pyranyl heterocycles. The usage of alpha,beta-unsaturated iminium salts is significant in controlling competing reaction pathways to give exclusively 2H-pyrans. Most significantly, experimental evidence is provided to support the mechanism of this reaction that involves a sequential Knoevenagel condensation and a reversible 6pi-electron electrocyclic ring-closure of 1-oxatrienes.
Subject(s)
Chemistry, Organic/methods , Ketones/chemistry , Pyrans/chemical synthesis , Pyrones/chemistry , Alkenes/chemistry , Catalysis , Crystallography, X-Ray , Cyclization , Imines/chemistry , Indicators and Reagents , Magnetic Resonance Spectroscopy , Molecular Structure , Oxidation-Reduction , Salts/chemical synthesis , StereoisomerismABSTRACT
The first asymmetric Ficini-Claisen rearrangement using chiral ynamides is described. At relatively low temperatures, the Ficini-Claisen rearrangement can be efficiently promoted by p-nitrobenzenesulfonic acid leading to high diastereoselectivity for a range of different allylic alcohols and chiral ynamides. [reaction: see text]