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
With structural guidance, tropane-derived HTS hits were modified to optimize for HSP90 inhibition and a desirable in vivo profile. Through an iterative SAR development process 12i (XL888) was discovered and shown to reduce HSP90 client protein content in PD studies. Furthermore, efficacy experiments performed in a NCI-N87 mouse xenograft model demonstrated tumor regression in some dosing regimens.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Azabicyclo Compounds/chemistry , Azabicyclo Compounds/therapeutic use , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Neoplasms/drug therapy , Phthalic Acids/chemistry , Phthalic Acids/therapeutic use , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Azabicyclo Compounds/pharmacokinetics , Azabicyclo Compounds/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Crystallography, X-Ray , Drug Discovery , HSP90 Heat-Shock Proteins/metabolism , Humans , Mice , Models, Molecular , Neoplasms/metabolism , Neoplasms/pathology , Phthalic Acids/pharmacokinetics , Phthalic Acids/pharmacologyABSTRACT
A series of substituted benzofuropyrimidinones with pan-PIM activities and excellent selectivity against a panel of diverse kinases is described. Initial exploration identified aryl benzofuropyrimidinones that were potent, but had cell permeability limitation. Using X-ray crystal structures of the bound PIM-1 complexes with 3, 5m, and 6d, we were able to guide the SAR and identify the alkyl benzofuropyrimidinone (6l) with good PIM potencies, permeability, and oral exposure.
Subject(s)
Drug Design , Furans/chemistry , Protein Kinase Inhibitors/chemical synthesis , Proto-Oncogene Proteins c-pim-1/antagonists & inhibitors , Pyrimidinones/chemistry , Binding Sites , Computer Simulation , Crystallography, X-Ray , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Structure, Tertiary , Proto-Oncogene Proteins c-pim-1/metabolism , Pyrimidinones/chemical synthesis , Pyrimidinones/pharmacology , Structure-Activity RelationshipABSTRACT
CDC7 is a serine/threonine kinase that has been shown to be required for the initiation and maintenance of DNA replication. Up-regulation of CDC7 is detected in multiple tumor cell lines, with inhibition of CDC7 resulting in cell cycle arrest. In this paper, we disclose the discovery of a potent and selective CDC7 inhibitor, XL413 (14), which was advanced into Phase 1 clinical trials. Starting from advanced lead 3, described in a preceding communication, we optimized the CDC7 potency and selectivity to demonstrate in vitro CDC7 dependent cell cycle arrest and in vivo tumor growth inhibition in a Colo-205 xenograft model.
Subject(s)
Cell Cycle Proteins/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyrimidinones/chemistry , Pyrimidinones/pharmacokinetics , Animals , Binding Sites , Cell Cycle Checkpoints/drug effects , Cell Cycle Proteins/metabolism , Cell Line, Tumor , Computer Simulation , Humans , Mice , Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/therapeutic use , Protein Serine-Threonine Kinases/metabolism , Protein Structure, Tertiary , Pyrimidinones/therapeutic use , Rats , Structure-Activity Relationship , Transplantation, Heterologous , Up-RegulationABSTRACT
Targeting glycosphingolipid synthesis has emerged as a novel approach for treating metabolic diseases. 32 (EXEL-0346) represents a new class of glucosylceramide synthase (GCS) inhibitors. This report details the elaboration of hit 8 with the goal of achieving and maintaining maximum GCS inhibition in vivo. 32 inhibited GCS with an IC(50) of 2 nM and achieved maximum hepatic GCS inhibition after four or five daily doses in rodents. Robust improvements in glucose tolerance in DIO mice and ZDF rats were observed after 2 weeks of q.d. dosing. Four weeks of dosing resulted in decreased plasma triglycerides and reduced hepatic fat deposition. Thus, 32 provides insight into the amount of metabolic regulation that can be restored following achievement of maximal target knockdown.
