Discovery of Mcl-1 inhibitors from integrated high throughput and virtual screening.

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.

Inhibitors of the anti-apoptotic Bcl-2 proteins: a patent review.

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.

An efficient 1,2-chelation-controlled reduction of protected hydroxy ketones via Red-Al.

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.

Efficient and selective reduction protocols of the 2,2-dimethyl-1,3-benzodioxan-4-one functional group to readily provide both substituted salicylaldehydes and 2-hydroxybenzyl alcohols.

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.