ABSTRACT
ATM inhibitors, such as 7, have demonstrated the antitumor potential of ATM inhibition when combined with DNA double-strand break-inducing agents in mouse xenograft models. However, the properties of 7 result in a relatively high predicted clinically efficacious dose. In an attempt to minimize attrition during clinical development, we sought to identify ATM inhibitors with a low predicted clinical dose (<50 mg) and focused on strategies to increase both ATM potency and predicted human pharmacokinetic half-life (predominantly through the increase of volume of distribution). These efforts resulted in the discovery of 64 (AZD0156), an exceptionally potent and selective inhibitor of ATM based on an imidazo[4,5- c]quinolin-2-one core. 64 has good preclinical phamacokinetics, a low predicted clinical dose, and a high maximum absorbable dose. 64 has been shown to potentiate the efficacy of the approved drugs irinotecan and olaparib in disease relevant mouse models and is currently undergoing clinical evaluation with these agents.
Subject(s)
Ataxia Telangiectasia Mutated Proteins/antagonists & inhibitors , Drug Design , Pyridines/pharmacokinetics , Quinolines/pharmacokinetics , Quinolones/pharmacology , Quinolones/pharmacokinetics , Administration, Oral , Ataxia Telangiectasia Mutated Proteins/chemistry , Ataxia Telangiectasia Mutated Proteins/metabolism , Biological Availability , Humans , Inhibitory Concentration 50 , Models, Molecular , Protein Conformation , Protein Kinase Inhibitors , Pyridines/administration & dosage , Pyridines/chemistry , Quinolines/administration & dosage , Quinolines/chemistry , Quinolones/administration & dosage , Quinolones/chemistry , Structure-Activity Relationship , Substrate SpecificityABSTRACT
Potent antagonists of the integrin α(5)ß(1), which are RGD mimetics built from tyrosine are described. This letter describes the optimization of in vitro potency obtained by variation of two parts of the molecule, the basic group and the linker between the basic group and the phenyl central core.
Subject(s)
Integrin alpha5beta1/antagonists & inhibitors , Oligopeptides/chemical synthesis , Tyrosine/analogs & derivatives , Tyrosine/chemical synthesis , Cell Adhesion/drug effects , Cell Survival/drug effects , Fibrinogen/chemistry , Fibronectins/chemistry , Humans , Integrin alpha5beta1/metabolism , K562 Cells , Models, Molecular , Molecular Mimicry , Oligopeptides/pharmacology , Serum Albumin/chemistry , Structure-Activity Relationship , Tyrosine/pharmacologyABSTRACT
Potent antagonists of the integrin α(5)ß(1), which are RGD mimetics built from tyrosine are described. This paper describes the optimization of in vitro potency obtained by variation of two parts of the molecule, the central aromatic core and the amide moiety.
