ABSTRACT
A novel class of Hsp90 inhibitors, structurally distinct from previously reported scaffolds, was developed from rational design and optimization of a compound library screen hit. These aminoquinazoline derivatives, represented by compound 15 (SNX-6833) or 1-(2-amino-4-methylquinazolin-7-yl)-3,6,6-trimethyl-6,7-dihydro-1H-indol-4(5H)-one, selectively bind to Hsp90 and inhibit its cellular activities at concentrations as low as single digit nanomolar.
Subject(s)
Antineoplastic Agents/chemical synthesis , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Indoles/chemical synthesis , Quinazolines/chemical synthesis , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation , Drug Discovery , Drug Screening Assays, Antitumor , HSP90 Heat-Shock Proteins/chemistry , Humans , Indoles/pharmacology , Models, Molecular , Protein Binding , Quinazolines/pharmacology , Small Molecule Libraries , Structure-Activity RelationshipABSTRACT
A novel class of heat shock protein 90 (Hsp90) inhibitors was developed from an unbiased screen to identify protein targets for a diverse compound library. These indol-4-one and indazol-4-one derived 2-aminobenzamides showed strong binding affinity to Hsp90, and optimized analogues exhibited nanomolar antiproliferative activity across multiple cancer cell lines. Heat shock protein 70 (Hsp70) induction and specific client protein degradation in cells on treatment with the inhibitors supported Hsp90 inhibition as the mechanism of action. Computational chemistry and X-ray crystallographic analysis of selected member compounds clearly defined the protein-inhibitor interaction and assisted the design of analogues. 4-[6,6-Dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2-[(trans-4-hydroxycyclohexyl)amino]benzamide (SNX-2112, 9) was identified as highly selective and potent (IC(50) Her2 = 11 nM, HT-29 = 3 nM); its prodrug amino-acetic acid 4-[2-carbamoyl-5-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-phenylamino]-cyclohexyl ester methanesulfonate (SNX-5422, 10) was orally bioavailable and efficacious in a broad range of xenograft tumor models (e.g. 67% growth delay in a HT-29 model) and is now in multiple phase I clinical trials.
Subject(s)
Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacology , Drug Discovery , HSP90 Heat-Shock Proteins/antagonists & inhibitors , ortho-Aminobenzoates/administration & dosage , ortho-Aminobenzoates/pharmacology , Administration, Oral , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Biological Availability , Cell Line, Tumor , Cell Proliferation/drug effects , Clinical Trials as Topic , Female , Heterocyclic Compounds, 4 or More Rings/chemistry , Heterocyclic Compounds, 4 or More Rings/pharmacokinetics , Heterocyclic Compounds, 4 or More Rings/pharmacology , Humans , Inhibitory Concentration 50 , Mice , Models, Molecular , Molecular Conformation , Prodrugs/pharmacokinetics , Substrate Specificity , ortho-Aminobenzoates/chemistry , ortho-Aminobenzoates/pharmacokineticsABSTRACT
In the course of our Heat Shock 90 program, certain carbazole compounds were identified which had an off-target antiproliferative activity. To understand the off-target activity, we studied one analog with strong activity. We discovered that it had an effect on tubulin polymerization kinetics and was competitive with colchicine. Additional analogs were made, and a number of potent compounds were identified.
Subject(s)
Antimitotic Agents/chemistry , Carbazoles/chemistry , Indoles/chemistry , Antimitotic Agents/chemical synthesis , Antimitotic Agents/pharmacology , Carbazoles/chemical synthesis , Carbazoles/pharmacology , Cell Line, Tumor , Colchicine/pharmacology , Drug Screening Assays, Antitumor , HSP90 Heat-Shock Proteins/metabolism , Humans , Indoles/chemical synthesis , Indoles/pharmacology , Tubulin/metabolismABSTRACT
Hsp90 maintains the conformational stability of multiple proteins implicated in oncogenesis and has emerged as a target for chemotherapy. We report here the discovery of a novel small molecule scaffold that inhibits Hsp90. X-ray data show that the scaffold binds competitively at the ATP site on Hsp90. Cellular proliferation and client assays demonstrate that members of the series are able to inhibit Hsp90 at nanomolar concentrations.
