Discovery of a Dual-Target Inhibitor of CDK7 and HDAC1 That Induces Apoptosis and Inhibits Migration in Colorectal Cancer.

Aberrant expression or dysfunction of cyclin-dependent kinase 7(CDK7) and histone deacetylase 1 (HDAC1) are associated with the occurrence and progression of various cancers. In this study, we developed a series of dual-target inhibitors by designing and synthesizing compounds that incorporate the pharmacophores of THZ2 and SAHA. The most potent dual-target inhibitor displayed robust inhibitory activity against several types of cancer cells and demonstrated promising inhibitory effects on both CDK7 and HDAC1. After further mechanistic studies, it was discovered that this inhibitor effectively arrested HCT-116 cells at the G2 phase and induced apoptosis. Additionally, it also significantly hindered the migration of HCT-116 cells and exhibited notable anti-tumor effects. These findings offer strong support for the development of dual-target inhibitors of CDK7 and HDAC1 and provide a promising avenue for future cancer therapy.

Targeting protein kinases for the treatment of Alzheimer's disease: Recent progress and future perspectives.

Alzheimer's disease (AD) is a serious neurodegenerative disease characterized by memory impairment, mental retardation, impaired motor balance, loss of self-care and even death. Among the complex and diverse pathological changes in AD, protein kinases are deeply involved in abnormal phosphorylation of Tau proteins to form intracellular neuronal fiber tangles, neuronal loss, extracellular ß-amyloid (Aß) deposits to form amyloid plaques, and synaptic disturbances. As a disease of the elderly, the growing geriatric population is directly driving the market demand for AD therapeutics, and protein kinases are potential targets for the future fight against AD. This perspective provides an in-depth look at the role of the major protein kinases (GSK-3ß, CDK5, p38 MAPK, ERK1/2, and JNK3) in the pathogenesis of AD. At the same time, the development of different protein kinase inhibitors and the current state of clinical advancement are also outlined.

Cellular mitophagy: Mechanism, roles in diseases and small molecule pharmacological regulation.

Cellular mitophagy means that cells selectively wrap and degrade damaged mitochondria through an autophagy mechanism, thus maintaining mitochondria and intracellular homeostasis. In recent years, mitophagy has received increasing attention as a research hotspot related to the pathogenesis of clinical diseases, such as neurodegenerative diseases, cardiovascular diseases, cancer, metabolic diseases, and so on. It has been found that the regulation of mitophagy may become a new direction for the treatment of some diseases. In addition, numerous small molecule modulators of mitophagy have also been reported, which provides new opportunities to comprehend the procedure and potential of therapeutic development. Taken together, in this review, we summarize current understanding of the mechanism of mitophagy, discuss the roles of mitophagy and its relationship with diseases, introduce the existing small-molecule pharmacological modulators of mitophagy and further highlight the significance of their development.