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1.
Cancer Cell ; 39(10): 1404-1421.e11, 2021 10 11.
Artículo en Inglés | MEDLINE | ID: mdl-34520734

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/inmunología
2.
J Med Chem ; 63(21): 12725-12747, 2020 11 12.
Artículo en Inglés | MEDLINE | ID: mdl-33054210

RESUMEN

The novel coronavirus disease COVID-19 that emerged in 2019 is caused by the virus SARS CoV-2 and named for its close genetic similarity to SARS CoV-1 that caused severe acute respiratory syndrome (SARS) in 2002. Both SARS coronavirus genomes encode two overlapping large polyproteins, which are cleaved at specific sites by a 3C-like cysteine protease (3CLpro) in a post-translational processing step that is critical for coronavirus replication. The 3CLpro sequences for CoV-1 and CoV-2 viruses are 100% identical in the catalytic domain that carries out protein cleavage. A research effort that focused on the discovery of reversible and irreversible ketone-based inhibitors of SARS CoV-1 3CLpro employing ligand-protease structures solved by X-ray crystallography led to the identification of 3 and 4. Preclinical experiments reveal 4 (PF-00835231) as a potent inhibitor of CoV-2 3CLpro with suitable pharmaceutical properties to warrant further development as an intravenous treatment for COVID-19.


Asunto(s)
Antivirales/farmacología , Proteasas 3C de Coronavirus/antagonistas & inhibidores , Cetonas/farmacología , Inhibidores de Proteasas/farmacología , SARS-CoV-2/efectos de los fármacos , Animales , Antivirales/síntesis química , Antivirales/metabolismo , Dominio Catalítico , Chlorocebus aethiops , Proteasas 3C de Coronavirus/química , Proteasas 3C de Coronavirus/metabolismo , Cristalografía por Rayos X , Humanos , Cetonas/síntesis química , Cetonas/metabolismo , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/metabolismo , Unión Proteica , Células Vero , Tratamiento Farmacológico de COVID-19
3.
Artículo en Inglés | MEDLINE | ID: mdl-15899596

RESUMEN

Liquid chromatography-mass spectrometry (LC-MS) has been used extensively in determination of the molecular weights of proteins, as well as covalent protein-ligand complexes. We have successfully developed LC-MS method for protein molecular weight measurement using small-bore and capillary LC-MS under acidic and basic conditions. A high pH method was critical in studying complexes that were unstable under acidic conditions. Microgram sensitivity was achieved using both methods. A protocol to study the binding mode of protein-ligand complexes under denaturing conditions was developed. These methods were applied to CP88 (a proprietary cysteine protease) inhibitors and revealed different binding modes of inhibitors to proteins that had similar non-reversible behavior in biochemical activity assays. The method also confirmed that one inhibitor studied binds to CP88 in a reversible covalent manner.


Asunto(s)
Cromatografía Liquida/métodos , Peso Molecular , Proteínas/antagonistas & inhibidores , Espectrometría de Masa por Ionización de Electrospray/métodos , Acetatos , Amoníaco , Tampones (Química) , Cromatografía Liquida/instrumentación , Cisteína Endopeptidasas/química , Inhibidores de Cisteína Proteinasa/química , Concentración de Iones de Hidrógeno , Ligandos , Unión Proteica
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