Undruggable proteins are a class of proteins that are often characterized by large, complex structures or functions that are difficult to interfere with using conventional drug design strategies. Targeting such undruggable targets has been considered also a great opportunity for treatment of human diseases and has attracted substantial efforts in the field of medicine. Therefore, in this review, we focus on the recent development of drug discovery targeting “undruggable” proteins and their application in clinic. To make this review well organized, we discuss the design strategies targeting the undruggable proteins, including covalent regulation, allosteric inhibition, protein–protein/DNA interaction inhibition, targeted proteins regulation, nucleic acid-based approach, immunotherapy and others.

Heat shock proteins are essential molecular chaperones that play crucial roles in stabilizing protein structures, facilitating the repair or degradation of damaged proteins, and maintaining proteostasis and cellular functions. Extensive research has demonstrated that heat shock proteins are highly expressed in cancers and closely associated with tumorigenesis and progression. The "Hallmarks of Cancer" are the core features of cancer biology that collectively define a series of functional characteristics acquired by cells as they transition from a normal state to a state of tumor growth, including sustained proliferative signaling, evasion of growth suppressors, resistance to cell death, enabled replicative immortality, the induction of angiogenesis, and the activation of invasion and metastasis. The pivotal roles of heat shock proteins in modulating the hallmarks of cancer through the activation or inhibition of various signaling pathways has been well documented. Therefore, this review provides an overview of the roles of heat shock proteins in vital biological processes from the perspective of the hallmarks of cancer and summarizes the small-molecule inhibitors that target heat shock proteins to regulate various cancer hallmarks. Moreover, we further discuss combination therapy strategies involving heat shock proteins and promising dual-target inhibitors to highlight the potential of targeting heat shock proteins for cancer treatment. In summary, this review highlights how targeting heat shock proteins could regulate the hallmarks of cancer, which will provide valuable information to better elucidate and understand the roles of heat shock proteins in oncology and the mechanisms of cancer occurrence and development and aid in the development of more efficacious and less toxic novel anticancer agents.

The relationship between gut microbiota and human health has gradually been recognized. Increasing studies show that the disorder of gut microbiota is related to the occurrence and development of many diseases. Metabolites produced by the gut microbiota are responsible for their extensive regulatory roles. In addition, naturally derived medicine food homology species with low toxicity and high efficiency have been clearly defined owing to their outstanding physiological and pharmacological properties in disease prevention and treatment. Based on supporting evidence, the current review summarizes the representative work of medicine food homology species targeting the gut microbiota to regulate host pathophysiology and discusses the challenges and prospects in this field. It aims to facilitate the understanding of the relationship among medicine food homology species, gut microbiota, and human health and further stimulate the advancement of more relevant research. As this review reveals, from the initial practical application to more mechanism studies, the relationship among medicine food homology species, gut microbiota, and human health has evolved into an irrefutable interaction. On the one hand, through affecting the population structure, metabolism, and function of gut microbiota, medicine food homology species maintain the homeostasis of the intestinal microenvironment and human health by affecting the population structure, metabolism, and function of gut microbiota. On the other hand, the gut microbiota is also involved in the bioconversion of the active ingredients from medicine food homology species and thus influences their physiological and pharmacological properties.

Here we report the synthesis of a library of chiral THIQ-fused spirooxindoles, which combine two privileged scaffolds in antitumor medicinal chemistry. Some of the library members inhibit the proliferation and invasion ability of Ras-mutated colon adenocarcinoma cells. Mechanistic studies suggest that the most potent compound, 3m, inhibits Ras-GTP and thereby suppresses downstream signaling mediated by MAPK, PI3K-Akt and Wnt. Ultimately this leads to mitochondrial apoptosis.

This review summarizes the recent development of novel approaches to construct structurally unique oxindoles featuring a spirocycle at the C2 position.

We have designed and synthesized a collection of chiral spirocyclic pyrazolone–ferrocene organometallic hybrids bearing multiple stereocenters and functional groups via organocatalysis. Compound 5b in this library displayed potent RalA inhibition, and it led to accumulation of reactive oxygen species and inhibited proliferation of pancreatic cancer cells. Molecular docking studies of 5b onto the RalA allosteric site suggest that it binds similarly to a C3 exoenzyme substrate peptide. This an efficient application of asymmetric organocatalysis in organometallic medicinal chemistry.