ABSTRACT
Hormones of the neurotrophin family, nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4), are known to activate the family of Tropomyosin receptor kinases (TrkA, TrkB, and TrkC). Moreover, inhibition of the TrkA kinase pathway in pain has been clinically validated by the NGF antibody tanezumab, leading to significant interest in the development of small molecule inhibitors of TrkA. Furthermore, Trk inhibitors having an acceptable safety profile will require minimal brain availability. Herein, we discuss the discovery of two potent, selective, peripherally restricted, efficacious, and well-tolerated series of pan-Trk inhibitors which successfully delivered three candidate quality compounds 10b, 13b, and 19. All three compounds are predicted to possess low metabolic clearance in human that does not proceed via aldehyde oxidase-catalyzed reactions, thus addressing the potential clearance prediction liability associated with our current pan-Trk development candidate PF-06273340.
Subject(s)
Drug Discovery , Pain/drug therapy , Protein Kinase Inhibitors/pharmacology , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Animals , Humans , Ligands , Molecular Docking Simulation , Protein Conformation , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/therapeutic use , Pyridines/chemistry , Pyridines/pharmacokinetics , Pyridines/pharmacology , Pyridines/therapeutic use , Rats , Receptor Protein-Tyrosine Kinases/chemistry , Receptor Protein-Tyrosine Kinases/metabolism , Solubility , Structure-Activity Relationship , Tissue DistributionABSTRACT
The c-Met pathway has been implicated in a variety of human cancers for its critical role in tumor growth, invasion, and metastasis. PF-04217903 is a novel ATP-competitive small-molecule inhibitor of c-Met kinase. PF-04217903 showed more than 1,000-fold selectivity for c-Met compared with more than 150 kinases, making it one of the most selective c-Met inhibitors described to date. PF-04217903 inhibited tumor cell proliferation, survival, migration/invasion in MET-amplified cell lines in vitro, and showed marked antitumor activity in tumor models harboring either MET gene amplification or a hepatocyte growth factor (HGF)/c-Met autocrine loop at well-tolerated dose levels in vivo. Antitumor efficacy of PF-04217903 was dose-dependent and showed a strong correlation with inhibition of c-Met phosphorylation, downstream signaling, and tumor cell proliferation/survival. In human xenograft models that express relatively high levels of c-Met, complete inhibition of c-Met activity by PF-04217903 only led to partial tumor growth inhibition (38%-46%) in vivo. The combination of PF-04217903 with Recepteur d'origine nantais (RON) short hairpin RNA (shRNA) knockdown in the HT29 model that also expresses activated RON kinase-induced tumor cell apoptosis and resulted in enhanced antitumor efficacy (77%) compared with either PF-04217903 (38%) or RON shRNA alone (56%). PF-04217903 also showed potent antiangiogenic properties in vitro and in vivo. Furthermore, PF-04217903 strongly induced phospho-PDGFRß (platelet-derived growth factor receptor) levels in U87MG xenograft tumors, indicating a possible oncogene switching mechanism in tumor cell signaling as a potential resistance mechanism that might compromise tumor responses to c-Met inhibitors. Collectively, these results show the use of highly selective inhibition of c-Met and provide insight toward targeting tumors exhibiting different mechanisms of c-Met dysregulation.
Subject(s)
Protein Kinase Inhibitors/pharmacology , Pyrazines/pharmacology , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Triazoles/pharmacology , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Female , Humans , Mice , Mice, Nude , Receptor Protein-Tyrosine Kinases/metabolism , Signal Transduction/drug effects , Xenograft Model Antitumor AssaysABSTRACT
Cyclin-dependent kinases (CDKs) are essential in the control of cell cycle progression. Inhibition of CDKs represents a new approach for pharmacological intervention in the treatment of a variety of proliferative diseases, especially cancer. Based on the crystal structure of CDK2 in complex with an imidazole indolinone compound 1 (SU9516), lead optimization through modeling, synthesis, and SAR studies has led to the discovery of a novel series of pyrrolyllactone and pyrrolyllactam indolinones as potent CDK2 inhibitors.
Subject(s)
CDC2-CDC28 Kinases/antagonists & inhibitors , Indoles/chemistry , Indoles/pharmacology , Lactams/chemistry , Lactones/chemistry , Adenosine Triphosphate/metabolism , Binding Sites , Cyclin-Dependent Kinase 2 , Drug Design , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Imidazoles/chemistry , Imidazoles/pharmacology , Inhibitory Concentration 50 , Lactams/pharmacology , Lactones/pharmacology , Models, Molecular , Structure-Activity RelationshipABSTRACT
Novel, potent, and highly selective classes of thrombin inhibitors were identified, which resulted from judicious combination of P4-aromatics and P2-P3-heterocyclic dipeptide surrogates with weakly basic (calcd pKa approximately non-basic-8.6) bicyclic P1-arginine mimics. The design, synthesis, and biological activity of achiral, non-covalent, orally bioavailable inhibitors NC1-NC44 featuring P1-indazoles, benzimidazoles, indoles, benzotriazoles, and aminobenzisoxazoles is disclosed.
Subject(s)
Bridged Bicyclo Compounds/chemical synthesis , Bridged Bicyclo Compounds/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Heterocyclic Compounds, 3-Ring/chemical synthesis , Heterocyclic Compounds, 3-Ring/pharmacology , Thrombin/antagonists & inhibitors , Animals , Area Under Curve , Biological Availability , Bridged Bicyclo Compounds/pharmacokinetics , Crystallography, X-Ray , Enzyme Inhibitors/pharmacokinetics , Heterocyclic Compounds, 3-Ring/pharmacokinetics , Indicators and Reagents , Rats , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
Investigations on P(2)-P(3)-heterocyclic dipeptide surrogates directed towards identification of an orally bioavailable thrombin inhibitor led us to pursue novel classes of achiral, non-covalent P(1)-arginine derivatives. The design, synthesis, and biological activity of inhibitors NC1-NC30 that feature three classes of monocyclic P(1)-arginine surrogates will be disclosed: (1) (hetero)aromatic amidines, amines and hydroxyamidines, (2) 2-aminopyrazines, and (3) 2-aminopyrimidines and 2-aminotetrahydropyrimidines.
