ABSTRACT
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
Small molecule (1) has been identified as a selective partial agonist of Opioid Receptor Like-1 (ORL-1) with potential utility for the treatment of anxiety and other disorders. Nociceptin (orphanin FQ) is an endogenous peptide ligand that binds to ORL-1, however it does not bind the classical δ, µ and κ opioid receptors with high affinity. The synthesis of 1 involved using a molecular diversity approach, to rapidly advance a library of compounds for biological testing. A lead selective potent partial agonist (35-fold ORL-1/Mu) progressed to ORL-1 (NOP or OP4) proof of concept testing in advanced studies. The synthetic approach and biological data for the related chemical series will be presented.
Subject(s)
Receptors, Opioid/agonists , Small Molecule Libraries/chemistry , Spiro Compounds/chemistry , Animals , Anxiety/drug therapy , Disease Models, Animal , Motor Activity/drug effects , Opioid Peptides/chemistry , Opioid Peptides/metabolism , Protein Binding , Rats , Receptors, Opioid/metabolism , Small Molecule Libraries/pharmacology , Small Molecule Libraries/therapeutic use , Spiro Compounds/pharmacology , Spiro Compounds/therapeutic use , Structure-Activity Relationship , Nociceptin Receptor , NociceptinABSTRACT
A novel series of indoles and 1H-pyrrolo[2,3-b]pyridines having a piperidine ring at the 3-position were synthesized and found to bind with high affinity to the ORL-1 receptor. Structure-activity relationships at the piperidine nitrogen were investigated in each series. Substitution on the phenyl ring and nitrogen atom of the indole and 1H-pyrrolo[2,3-b]pyridine cores generated several selective high-affinity ligands that were agonists of the ORL-1 receptor.
Subject(s)
Indoles/pharmacology , Piperidines/pharmacology , Pyridines/pharmacology , Pyrroles/pharmacology , Receptors, Opioid/agonists , Binding Sites , Indoles/chemical synthesis , Indoles/chemistry , Ligands , Molecular Structure , Piperidines/chemical synthesis , Piperidines/chemistry , Pyridines/chemistry , Pyrroles/chemical synthesis , Pyrroles/chemistry , Structure-Activity Relationship , Nociceptin ReceptorABSTRACT
A novel series of indolin-2-ones having a spirocyclic piperidine ring at the 3-position was synthesized and found to bind with high affinity to the ORL-1 receptor. Structure-activity relationships at the piperidine nitrogen were investigated. Substitution on the phenyl ring and nitrogen atom of the indolin-2-one core generated several selective high-affinity ligands that were antagonists of the ORL-1 receptor.
