ABSTRACT
The CDK4/6 inhibitor, palbociclib (PAL), significantly improves progression-free survival in HR+/HER2- breast cancer when combined with anti-hormonals. We sought to discover PAL resistance mechanisms in preclinical models and through analysis of clinical transcriptome specimens, which coalesced on induction of MYC oncogene and Cyclin E/CDK2 activity. We propose that targeting the G1 kinases CDK2, CDK4, and CDK6 with a small-molecule overcomes resistance to CDK4/6 inhibition. We describe the pharmacodynamics and efficacy of PF-06873600 (PF3600), a pyridopyrimidine with potent inhibition of CDK2/4/6 activity and efficacy in multiple in vivo tumor models. Together with the clinical analysis, MYC activity predicts (PF3600) efficacy across multiple cell lineages. Finally, we find that CDK2/4/6 inhibition does not compromise tumor-specific immune checkpoint blockade responses in syngeneic models. We anticipate that (PF3600), currently in phase 1 clinical trials, offers a therapeutic option to cancer patients in whom CDK4/6 inhibition is insufficient to alter disease progression.
Subject(s)
Cell Cycle/drug effects , Cyclin-Dependent Kinase 2/antagonists & inhibitors , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Cyclin-Dependent Kinase 6/antagonists & inhibitors , Neoplasms/drug therapy , Female , Humans , Male , Neoplasms/immunologyABSTRACT
A series of novel pyridine-3-propanoic acids was synthesized. A structure-activity relationship study of these compounds led to the identification of potent dual PPARalpha/gamma agonists with varied isoform selectivity. Based on the results of efficacy studies in diabetic (db/db) mice, and the desired pharmacokinetic parameters, compounds (S)-14 and (S)-19 were selected for further profiling.
Subject(s)
Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/pharmacology , PPAR alpha/agonists , PPAR gamma/agonists , Pyridines/blood , Pyridines/pharmacology , Animals , Blood Glucose/metabolism , Body Weight/drug effects , Cell Line, Tumor , Diabetes Mellitus/blood , Diabetes Mellitus/drug therapy , Diabetes Mellitus/pathology , Ether/chemistry , Humans , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/therapeutic use , Mice , Molecular Structure , PPAR alpha/metabolism , PPAR gamma/metabolism , Pyridines/chemical synthesis , Pyridines/therapeutic use , Structure-Activity Relationship , Thiazolidinediones/chemistryABSTRACT
The structure-based design, chemical synthesis, and biological evaluation of novel MTAP substrates are described. These compounds incorporate various C5'-moieties and are shown to have different k(cat)/K(m) values compared with the natural MTAP substrate (MTA).
Subject(s)
Purine-Nucleoside Phosphorylase/metabolism , Drug Design , Humans , Molecular Structure , Substrate SpecificityABSTRACT
A detailed account regarding a formal [3 + 3] cycloaddition method using 4-hydroxy-2-pyrones and 1,3-diketones is described here. This formal cycloaddition reaction or annulation reaction is synthetically useful for constructing 2H-pyranyl heterocycles. The usage of alpha,beta-unsaturated iminium salts is significant in controlling competing reaction pathways to give exclusively 2H-pyrans. Most significantly, experimental evidence is provided to support the mechanism of this reaction that involves a sequential Knoevenagel condensation and a reversible 6pi-electron electrocyclic ring-closure of 1-oxatrienes.
