ABSTRACT
An extension of our previously reported series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. Addition of a second methyl group to the tether provided analogs that show increased potency in binding as well as cell-proliferation assays and, more importantly, are stable toward microsomes. We wish to disclose the discovery of a macrocycle which showed impressive biomarker activity 24-h post dosing and which demonstrated prolonged exposure in tumors. When studied in a lung cancer xenograft model, the compound demonstrated significant tumor size reduction.
Subject(s)
Antineoplastic Agents/chemistry , Benzamides/chemistry , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Lung Neoplasms/drug therapy , Macrocyclic Compounds/chemistry , Administration, Oral , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Benzamides/pharmacokinetics , Benzamides/therapeutic use , Binding Sites , Biomarkers/metabolism , Drug Evaluation, Preclinical , HSP90 Heat-Shock Proteins/metabolism , Humans , Mice , Mice, Nude , Microsomes, Liver/metabolism , Protein Structure, Tertiary , Rats , Transplantation, HeterologousABSTRACT
A novel series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. In continuation of our research in this area, macrocyclic amides and lactams were explored to reduce the risk of hERG liabilities. This effort culminated in the discovery of compound 38, which showed a favorable in vitro profile, and efficiently suppressed proliferation of several relevant cell lines. This compound showed prolonged Hsp90-inhibitory activity at least 24 h post-administration, consistent with elevated and prolonged exposure in the tumor.
Subject(s)
Antineoplastic Agents/pharmacology , Biomarkers/metabolism , Drug Design , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Lactams, Macrocyclic/chemical synthesis , Lactams, Macrocyclic/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Crystallography, X-Ray , Fluorescent Dyes/chemical synthesis , Fluorescent Dyes/chemistry , Fluorescent Dyes/pharmacology , Humans , Inhibitory Concentration 50 , Lactams, Macrocyclic/chemistry , Models, Molecular , Molecular Structure , ortho-Aminobenzoates/chemical synthesis , ortho-Aminobenzoates/chemistry , ortho-Aminobenzoates/pharmacologyABSTRACT
The series of 4-(benzylaminomethylene)isoquinoline-1,3-(2H,4H)-dione and 4-[(pyridylmethyl)aminomethylene]isoquinoline-1,3-(2H,4H)-dione derivatives reported here represents a novel class of potential antitumor agents, which potently and selectively inhibit CDK4 over CDK2 and CDK1. In the benzylamino headpiece, a 3-OH substituent is required on the phenyl ring for CDK4 inhibitory activity, which is further enhanced when an iodo, aryl, heteroaryl, t-butyl, or cyclopentyl substituent is introduced at the C-6 position of the isoquinoline-1,3-dione core. To circumvent the metabolic liability associated with the phenolic OH group on the 4-substituted 3-OH phenyl headpiece, we take two approaches: first, introduce a nitrogen o- or p- to the 3-OH group in the phenyl ring; second, replace the phenyl headpiece with N-substituted 2-pyridones. We present here the synthesis, SAR data, metabolic stability data, and a CDK4 mimic model that explains the binding, potency, and selectivity of our CDK4 selective inhibitors.
Subject(s)
Antineoplastic Agents/chemical synthesis , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Isoquinolines/chemical synthesis , Pyridines/chemical synthesis , Adenosine Triphosphate/metabolism , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Binding Sites , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Humans , Hydrogen Bonding , In Vitro Techniques , Isoquinolines/chemistry , Isoquinolines/pharmacology , Microsomes, Liver/metabolism , Models, Molecular , Phosphorylation , Pyridines/chemistry , Pyridines/pharmacology , Rats , Retinoblastoma Protein/metabolism , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The cyclin-dependent kinases (CDKs), as complexes with their respective partners, the cyclins, are critical regulators of cell cycle progression. Because aberrant regulations of CDK4/cyclin D1 lead to uncontrolled cell proliferation, a hallmark of cancer, small-molecule inhibitors of CDK4/cyclin D1 are attractive as prospective antitumor agents. The series of 4-(phenylaminomethylene)isoquinoline-1,3(2H,4H)-dione derivatives reported here represents a novel class of potent inhibitors that selectively inhibit CDK4 over CDK2 and CDK1 activities. In the headpiece of the 4-(phenylaminomethylene)isoquinoline-1,3(2H,4H)-dione, a basic amine substituent is required on the aniline ring for the CDK4 inhibitory activity. The inhibitory activity is further enhanced when an aryl or heteroaryl substituent is introduced at the C-6 position of the isoquinoline-1,3(2H,4H)-dione core. We present here SAR data and a CDK4 mimic model that explains the binding, potency, and selectivity of our CDK4 selective inhibitors.
