RESUMEN
Protein-protein interactions (PPIs) represent important and promising therapeutic targets that are associated with the regulation of various molecular pathways, particularly in cancer. Although they were once considered "undruggable," the recent advances in screening strategies, structure-based design, and elucidating the nature of hot spots on PPI interfaces, have led to the discovery and development of successful small-molecule inhibitors. In this report, we are describing an integrated high-throughput and computational screening approach to enable the discovery of small-molecule PPI inhibitors of the anti-apoptotic protein, Mcl-1. Applying this strategy, followed by biochemical, biophysical, and biological characterization, nineteen new chemical scaffolds were discovered and validated as Mcl-1 inhibitors. A novel series of Mcl-1 inhibitors was designed and synthesized based on the identified difuryl-triazine core scaffold and structure-activity studies were undertaken to improve the binding affinity to Mcl-1. Compounds with improved in vitro binding potency demonstrated on-target activity in cell-based studies. The obtained results demonstrate that structure-based analysis complements the experimental high-throughput screening in identifying novel PPI inhibitor scaffolds and guides follow-up medicinal chemistry efforts. Furthermore, our work provides an example that can be applied to the analysis of available screening data against numerous targets in the PubChem BioAssay Database, leading to the identification of promising lead compounds, fuelling drug discovery pipelines.
Asunto(s)
Proteína 1 de la Secuencia de Leucemia de Células Mieloides/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Simulación por Computador , Ensayos de Selección de Medicamentos Antitumorales , Ensayos Analíticos de Alto Rendimiento , Humanos , Modelos Moleculares , Simulación del Acoplamiento Molecular , Estructura Molecular , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/química , Bibliotecas de Moléculas Pequeñas/química , Relación Estructura-ActividadRESUMEN
INTRODUCTION: The B-cell lymphoma-2 (Bcl-2) family of proteins is central to the regulation of apoptosis, which is vital for proper tissue development and cellular homeostasis. Anti-apoptotic proteins, members of the Bcl-2 family, are an important survival factor for many cancers and their overexpression has been associated with tumor initiation, progression, and resistance to current anticancer therapies. Therefore, strategies seeking to antagonize the function of Bcl-2 anti-apoptotic proteins have been extensively studied for developing a novel cancer therapy. AREAS COVERED: This review covers research and patent literature of the last 15 years dealing with the discovery and development of inhibitors of the Bcl-2 protein family. EXPERT OPINION: The feasibility of disrupting protein-protein interactions between anti-apoptotic and pro-apoptotic proteins, members of the Bcl-2 family, using peptidomimetics and small-molecule inhibitors has been successfully established. Three small-molecule inhibitors have entered human clinical trials, which will allow the evaluation of this potential therapeutic approach in cancer patients. It will be important to gain a better understanding of pan and selective Bcl-2 inhibitors in order to facilitate future drug design efforts.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Animales , Apoptosis/efectos de los fármacos , Diseño de Fármacos , Resistencia a Antineoplásicos , Humanos , Peptidilprolil Isomerasa de Interacción con NIMA , Neoplasias/patología , Patentes como Asunto , Peptidomiméticos/farmacología , Isomerasa de Peptidilprolil/metabolismoRESUMEN
In this paper, we have demonstrated that Red-Al is an efficient chelation-controlled reducing reagent for acyclic acetal (i.e., MOM, MEM, SEM, and BOM) protected alpha-hydroxy ketones. Typically, diastereomeric ratios (dr) ranged from 5 to 20:1 for the 1,2- anti-diols in good to excellent yields.
Asunto(s)
Quelantes/química , Cetonas/química , Compuestos Organometálicos/química , Hidroxilación , Estructura Molecular , Oxidación-ReducciónRESUMEN
Two complementary procedures have been developed that selectively allow for the synthesis of either substituted salicylaldehydes or the corresponding 2-hydroxylbenzyl alcohols upon treatment of the 2,2-dimethyl-1,3-benzodioxan-4-one functional group with DIBAL-H or LAH, respectively.