Insight into small-molecule inhibitors targeting extracellular nucleotide pyrophosphatase/phosphodiesterase1 for potential multiple human diseases.

Extracellular nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) has been identified as a type II transmembrane glycoprotein. It plays a crucial role in various biological processes, such as bone mineralization, cancer cell proliferation, and immune regulation. Consequently, ENPP1 has garnered attention as a promising target for pharmacological interventions. Despite its potential, the development of clinical-stage ENPP1 inhibitors for solid tumors, diabetes, and silent rickets remains limited. However, there are encouraging findings from preclinical trials involving small molecules exhibiting favorable therapeutic effects and safety profiles. This perspective aims to shed light on the structural properties, biological functions and the relationship between ENPP1 and diseases. Additionally, it focuses on the structure-activity relationship of ENPP1 inhibitors, with the intention of guiding the future development of new and effective ENPP1 inhibitors.

Technologies of targeting histone deacetylase in drug discovery: Current progress and emerging prospects.

Histone deacetylases (HDACs) catalyze the hydrolysis of acetyl-l-lysine side chains in histones and non-histones, which are key to epigenetic regulation in humans. Targeting HDACs has emerged as a promising strategy for treating various types of cancer, including myeloma and hematologic malignancies. At present, numerous small molecule inhibitors targeting HDACs are actively being investigated in clinical trials. Despite their potential efficacy in cancer treatment, HDAC inhibitors suffer from multi-directional selectivity and preclinical resistance issues. Hence, developing novel inhibitors based on cutting-edge medicinal chemistry techniques is essential to overcome these limitations and improve clinical outcomes. This manuscript presents an extensive overview of the properties and biological functions of HDACs in cancer, provides an overview of the current state of development and limitations of clinical HDAC inhibitors, and analyzes a range of innovative medicinal chemistry techniques that are applied. These techniques include selective inhibitors, dual-target inhibitors, proteolysis targeting chimeras, and protein-protein interaction inhibitors.