ABSTRACT
The elaboration of a novel scaffold for the inhibition of JAK2 and FAK kinases was targeted in order to provide a dual inhibitor that could target divergent pathways for tumor cell progression.
Subject(s)
Focal Adhesion Protein-Tyrosine Kinases/chemistry , Janus Kinase 2/chemistry , Protein Kinase Inhibitors/pharmacology , Animals , Cell Line, Tumor , Chemistry, Pharmaceutical/methods , Disease Progression , Drug Design , Humans , Inhibitory Concentration 50 , Mice , Models, Chemical , Mutation , Neoplasms/genetics , Neoplasms/pathology , Protein Kinase Inhibitors/chemical synthesis , Rats , Rats, Sprague-Dawley , Signal Transduction , Time FactorsABSTRACT
Chemical strategies to mitigate cytochrome P450-mediated bioactivation of novel 2,7-disubstituted pyrrolo[2,1-f][1,2,4]triazine ALK inhibitors are described along with synthesis and biological activity. Piperidine-derived analogues showing minimal microsomal reactive metabolite formation were discovered. Potent, selective, and metabolically stable ALK inhibitors from this class were identified, and an orally bioavailable compound (32) with antitumor efficacy in ALK-driven xenografts in mouse models was extensively characterized.
Subject(s)
Aniline Compounds/chemical synthesis , Antineoplastic Agents/chemical synthesis , Pyrroles/chemical synthesis , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Triazines/chemical synthesis , Administration, Oral , Anaplastic Lymphoma Kinase , Aniline Compounds/pharmacokinetics , Aniline Compounds/pharmacology , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Biological Availability , In Vitro Techniques , Mice , Mice, SCID , Microsomes, Liver/metabolism , Pyrroles/pharmacokinetics , Pyrroles/pharmacology , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Triazines/pharmacokinetics , Triazines/pharmacology , Xenograft Model Antitumor AssaysABSTRACT
The JAK2/STAT pathway has important roles in hematopoiesis. With the discovery of the JAK2 V617F mutation and its presence in many patients with myeloproliferative neoplasms, research in the JAK2 inhibitor arena has dramatically increased. We report a novel series of potent JAK2 inhibitors containing a 2,7-pyrrolotriazine core. To minimize potential drug-induced toxicity, targets were analyzed for the ability to form a glutathione adduct. Glutathione adduct formation was decreased by modification of the aniline substituent at C2.
Subject(s)
Janus Kinase 2/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Pyrroles/chemistry , Triazines/metabolism , Amino Acid Substitution , Glutathione/chemistry , Humans , Janus Kinase 2/genetics , Janus Kinase 2/metabolism , Myeloproliferative Disorders/metabolism , Protein Kinase Inhibitors/pharmacokinetics , Structure-Activity Relationship , Triazines/chemistryABSTRACT
A novel 2,7-disubstituted-pyrrolo[2,1-f][1,2,4]triazine scaffold has been designed as a new kinase inhibitor platform mimicking the bioactive conformation of the well-known diaminopyrimidine motif. The design, synthesis, and validation of this new pyrrolo[2,1-f][1,2,4]triazine scaffold will be described for inhibitors of anaplastic lymphoma kinase (ALK). Importantly, incorporation of appropriate potency and selectivity determinants has led to the discovery of several advanced leads that were orally efficacious in animal models of anaplastic large cell lymphoma (ALCL). A lead inhibitor (30) displaying superior efficacy was identified and in depth in vitro/in vivo characterization will be presented.
Subject(s)
Antineoplastic Agents/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Pyrroles/chemical synthesis , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Sulfonamides/chemical synthesis , Triazines/chemical synthesis , Anaplastic Lymphoma Kinase , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/pharmacokinetics , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Cell Line, Tumor , Cell Membrane Permeability , Drug Screening Assays, Antitumor , Humans , In Vitro Techniques , Lymphoma, Large-Cell, Anaplastic/drug therapy , Mice , Mice, SCID , Microsomes, Liver/metabolism , Models, Molecular , Neoplasm Transplantation , Pyrroles/pharmacokinetics , Pyrroles/pharmacology , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Sulfonamides/pharmacokinetics , Sulfonamides/pharmacology , Transplantation, Heterologous , Triazines/pharmacokinetics , Triazines/pharmacologyABSTRACT
We have developed a novel series of potent and selective factor Xa inhibitors that employ a key 7-fluoroindazolyl moiety. The 7-fluoro group on the indazole scaffold replaces the carbonyl group of an amide that is found in previously reported factor Xa inhibitors. The structure of a factor Xa cocrystal containing 7-fluoroindazole 51a showed the 7-fluoro atom hydrogen-bonding with the N-H of Gly216 (2.9 A) in the peptide backbone. Thus, the 7-fluoroindazolyl moiety not only occupied the same space as the carbonyl group of an amide found in prior factor Xa inhibitors but also maintained a hydrogen bond interaction with the protein's beta-sheet domain. The structure-activity relationship for this series was consistent with this finding, as the factor Xa inhibitory potencies were about 60-fold greater (DeltaDelta G approximately 2.4 kcal/mol) for the 7-fluoroindazoles 25a and 25c versus the corresponding indazoles 25b and 25d. Highly convergent synthesis of these factor Xa inhibitors is also described.
