RESUMEN
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.
Asunto(s)
Ciclo Celular/efectos de los fármacos , Quinasa 2 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Femenino , Humanos , Masculino , Neoplasias/inmunologíaRESUMEN
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.
Asunto(s)
Hipoglucemiantes/síntesis química , Hipoglucemiantes/farmacología , PPAR alfa/agonistas , PPAR gamma/agonistas , Piridinas/sangre , Piridinas/farmacología , Animales , Glucemia/metabolismo , Peso Corporal/efectos de los fármacos , Línea Celular Tumoral , Diabetes Mellitus/sangre , Diabetes Mellitus/tratamiento farmacológico , Diabetes Mellitus/patología , Éter/química , Humanos , Hipoglucemiantes/química , Hipoglucemiantes/uso terapéutico , Ratones , Estructura Molecular , PPAR alfa/metabolismo , PPAR gamma/metabolismo , Piridinas/síntesis química , Piridinas/uso terapéutico , Relación Estructura-Actividad , Tiazolidinedionas/químicaRESUMEN
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).
Asunto(s)
Purina-Nucleósido Fosforilasa/metabolismo , Diseño de Fármacos , Humanos , Estructura Molecular , Especificidad por SustratoRESUMEN
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.
