ABSTRACT
A series of novel, highly potent, selective, and ATP-competitive mammalian target of rapamycin (mTOR) inhibitors based on a benzoxazepine scaffold have been identified. Lead optimization resulted in the discovery of inhibitors with low nanomolar activity and greater than 1000-fold selectivity over the closely related PI3K kinases. Compound 28 (XL388) inhibited cellular phosphorylation of mTOR complex 1 (p-p70S6K, pS6, and p-4E-BP1) and mTOR complex 2 (pAKT (S473)) substrates. Furthermore, this compound displayed good pharmacokinetics and oral exposure in multiple species with moderate bioavailability. Oral administration of compound 28 to athymic nude mice implanted with human tumor xenografts afforded significant and dose-dependent antitumor activity.
Subject(s)
Adenosine Triphosphate/metabolism , Binding, Competitive , Drug Discovery , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/pharmacology , TOR Serine-Threonine Kinases/antagonists & inhibitors , TOR Serine-Threonine Kinases/metabolism , Administration, Oral , Animals , Benzoxazines/chemistry , Benzoxazines/metabolism , Benzoxazines/pharmacokinetics , Benzoxazines/pharmacology , Biological Availability , Cell Line, Tumor , Dogs , Female , Humans , Male , Mice , Models, Molecular , Protein Conformation , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacokinetics , Rats , Substrate Specificity , TOR Serine-Threonine Kinases/chemistryABSTRACT
We report the discovery of a series of 4-aryl-2-aminoalkylpyrimidine derivatives as potent and selective JAK2 inhibitors. High throughput screening of our in-house compound library led to the identification of hit 1, from which optimization resulted in the discovery of highly potent and selective JAK2 inhibitors. Advanced lead 10d demonstrated a significant dose-dependent pharmacodynamic and antitumor effect in a mouse xenograft model. Based upon the desirable profile of 10d (XL019) it was advanced into clinical trials.
Subject(s)
Antineoplastic Agents/pharmacology , Janus Kinase 2/antagonists & inhibitors , Neoplasms, Experimental/drug therapy , Proline/analogs & derivatives , Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacology , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Proliferation/drug effects , Crystallography, X-Ray , Dogs , Dose-Response Relationship, Drug , Haplorhini , High-Throughput Screening Assays , Janus Kinase 2/metabolism , Mice , Mice, Nude , Models, Molecular , Molecular Structure , Neoplasms, Experimental/pathology , Proline/administration & dosage , Proline/chemistry , Proline/pharmacology , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemistry , Pyrimidines/administration & dosage , Pyrimidines/chemistry , Rats , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
We have synthesized and evaluated a series of tetramic acid-based and hydroxyquinolinone-based inhibitors of plasminogen activator inhibitor-1 (PAI-1). These studies resulted in the identification of several compounds which showed excellent potency against PAI-1. The design, synthesis and SAR of these compounds are described.
