Current Medicinal Chemistry - Volume 30, Issue 27, 2023

Protein lysine methylation is a significant protein post-translational modification (PTMs) and has a key function in epigenetic regulation. Protein lysine methyltransferase (PKMTs) mainly catalyzes the lysine methylation of various core histones and a few non-histone proteins. It has been observed that aberrant activity of PKMTs has been found in many cancers and other diseases, and some PKMT inhibitors have been discovered and progressed to clinical trials. This field developed rapidly and has aroused great interest. In this paper, we reviewed the biochemical and biological activities of PKMTs and their association with various cancers. Selective small-molecule inhibitors, including their chemical structure, structure-activity relationship, and in vitro/vivo studies, are also described to provide ideas for the discovery of highly potent, selective PKMT inhibitors.

Melatonin, mainly released from the pineal gland, also produced in the reproductive organs and cells, plays important roles in rhythms of the sleep-wake cycle, retardation of ageing processes, and antioxidant/anti-inflammatory functions. As a key mediator in reproductive systems, melatonin is participated in the reproductive process via regulating gamete and embryo development and influences reproductive diseases and pregnancy outcomes. The underlying mechanisms include epigenetic and other regulations, which are interesting for exploring new targets in the prevention and treatment of reproductive diseases. This review discusses the relationship between melatonin and reproductive functions and dysfunction, as well as potential clinical applications of melatonin in reproductive medicine. Notably, Developmental Origins of Health and Diseases (DOHaD) is closely linked to reproduction, this article is the first to review the new progress in studies on the possible relationship between melatonin and DOHaD.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial hyperplasia and joint damage. Systemic complications and progressive disability are burdens that lead to a significant socio-economic costs in patients with RA. Current RA biomarkers used in predicting, diagnosing, and monitoring the treatment of the disease have not been very successful. Moreover, only 60% of patients show a satisfactory response to current biological and conventional therapies. Studies on immunometabolism have suggested that dysregulated enzymes, transcription factors, metabolites, and metabolic pathways could be considered potential therapeutic targets for the treatment of RA. Factors such as the high concentration of various intermediate molecules arising from metabolism, hypoxia, lack of nutrients, and other metabolic alterations affect local immune responses and preserve a state of chronic inflammation in synovial tissues. Fortunately, in vitro and in vivo studies have shown that targeting specific metabolic pathways is associated with a decreased level of inflammation. Specifically, targeting metabolic intermediates, such as succinate or lactate, has shown promising clinical outcomes in RA treatment. These findings open an avenue for the identification of novel biomarkers for diagnosis, prognosis, and determining the success of various treatments in RA patients, as well as the discovery of new therapeutic targets.

Targeted protein degradation (TPD) strategies have become a new trend in drug discovery due to the capability of triggering the degradation of protein of interest (POI) selectively and effectively in recent decades. Particularly, the hydrophobic tag tethering degrader (HyTTD) has drawn a lot of attention and may offer a promising strategy for new drug research and development in the future. Herein, we will give an overview of the development of HyTTD, the structure-activity relationship (SAR) between HyTTD and linkers, HyTs, and ligand motifs, as well as the various HyTTDs targeting different targets, thus offering a rational strategy for the design of HyTTDs in further TPD drug discovery.