ABSTRACT
Resistance to androgen receptor (AR) blockade in castration-resistant prostate cancer (CRPC) is associated with sustained AR signaling, including through alternative splicing of AR (AR-SV). Inhibitors of transcriptional coactivators that regulate AR activity, including the paralog histone acetyltransferase proteins p300 and CBP, are attractive therapeutic targets for lethal prostate cancer. Herein, we validate targeting p300/CBP as a therapeutic strategy for lethal prostate cancer and describe CCS1477, a novel small-molecule inhibitor of the p300/CBP conserved bromodomain. We show that CCS1477 inhibits cell proliferation in prostate cancer cell lines and decreases AR- and C-MYC-regulated gene expression. In AR-SV-driven models, CCS1477 has antitumor activity, regulating AR and C-MYC signaling. Early clinical studies suggest that CCS1477 modulates KLK3 blood levels and regulates CRPC biopsy biomarker expression. Overall, CCS1477 shows promise for the treatment of patients with advanced prostate cancer. SIGNIFICANCE: Treating CRPC remains challenging due to persistent AR signaling. Inhibiting transcriptional AR coactivators is an attractive therapeutic strategy. CCS1477, an inhibitor of p300/CBP, inhibits growth and AR activity in CRPC models, and can affect metastatic CRPC target expression in serial clinical biopsies.See related commentary by Rasool et al., p. 1011.This article is highlighted in the In This Issue feature, p. 995.
Subject(s)
Androgen Receptor Antagonists/therapeutic use , Imidazoles/therapeutic use , Oxazoles/therapeutic use , Prostatic Neoplasms, Castration-Resistant/drug therapy , p300-CBP Transcription Factors/antagonists & inhibitors , Androgen Receptor Antagonists/pharmacology , Animals , Cell Line, Tumor/drug effects , Cell Proliferation/drug effects , Humans , Imidazoles/pharmacology , Male , Mice , Oxazoles/pharmacology , Xenograft Model Antitumor AssaysABSTRACT
A ligand-based virtual screening exercise examining likely bioactive conformations of AM 580 (2) and AGN 193836 (3) was used to identify the novel, less lipophilic RARα agonist 4-(3,5-dichloro-4-ethoxybenzamido)benzoic acid 5, which has good selectivity over the RARß, and RARγ receptors. Analysis of the medicinal chemistry parameters of the 3,5-substituents of derivatives of template 5 enabled us to design a class of drug-like molecules with lower intrinsic clearance and higher oral bioavailability which led to the novel RARα agonist 4-(3-chloro-4-ethoxy-5-isopropoxybenzamido)-2-methylbenzoic acid 56 that has high RARα potency and excellent selectivity versus RARß (2 orders of magnitude) and RARγ (4 orders of magnitude) at both the human and mouse RAR receptors with improved drug-like properties. This RARα specific agonist 56 has high oral bioavailability (>80%) in both mice and dogs with a good PK profile and was shown to be inactive in cytotoxicity and genotoxicity screens.
Subject(s)
Aminobenzoates/chemistry , Benzoates/chemistry , Drug Design , Retinoic Acid Receptor alpha/agonists , Tetrahydronaphthalenes/chemistry , Administration, Oral , Aminobenzoates/pharmacokinetics , Aminobenzoates/toxicity , Animals , Benzoates/pharmacokinetics , Benzoates/toxicity , COS Cells , Cell Survival/drug effects , Chlorocebus aethiops , Half-Life , Hep G2 Cells , Humans , Mice , Microsomes, Liver/metabolism , Rats , Receptors, Retinoic Acid/agonists , Receptors, Retinoic Acid/metabolism , Retinoic Acid Receptor alpha/metabolism , Structure-Activity Relationship , Tetrahydronaphthalenes/pharmacokinetics , Tetrahydronaphthalenes/toxicity , Retinoic Acid Receptor gammaABSTRACT
The discovery of a novel series of therapeutic agents that has been designed and optimized for treating chronic obstructive pulmonary disease is reported. The pharmacological strategy was based on the identification of compounds that inhibit a defined subset of kinase enzymes modulating inflammatory processes that would be effective against steroid refractory disease and exhibit a sustained duration of action after inhaled delivery.
Subject(s)
Asthma/drug therapy , Drug Discovery , Protein Kinase Inhibitors/pharmacology , Protein Kinases/metabolism , Pulmonary Disease, Chronic Obstructive/drug therapy , Animals , Asthma/metabolism , Dose-Response Relationship, Drug , Drug Resistance/drug effects , Humans , Male , Mice , Mice, Inbred Strains , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pulmonary Disease, Chronic Obstructive/metabolism , Steroids/pharmacology , Structure-Activity Relationship , U937 CellsABSTRACT
Lanciaquinone, isolated from Maesa lanceolata, was originally assigned as a bisbenzoquinone with a C14-chain linking the two quinone rings. A synthesis of the reported structure, in which the key step is a double Claisen rearrangement, suggests that the structure of the natural product needs to be revised.
Subject(s)
Benzoquinones/chemical synthesis , Primulaceae/chemistry , Benzoquinones/chemistry , Benzoquinones/isolation & purification , Magnetic Resonance Spectroscopy , Molecular StructureABSTRACT
A simple and efficient synthesis of 6-chloro-2-iodopurine from hypoxanthine has been achieved. This strategy relied on a regiospecific lithiation/quenching sequence of 6-chloro-9-(tetrahydropyran-2-yl)purine using Harpoon's base and tributyltin chloride. HMBC NMR studies on the product and intermediates confirmed the regioselectivity of this methodology. The molecular structures of the final dihalogenopurine and its 9-protected precursor were determined by single crystal X-ray diffraction.
