Search

Proteolytic targeting chimaeras (PROTACs) have been developed as an effective technology for targeted protein degradation. PROTACs are heterobifunctional molecules that can trigger the polyubiquitination of proteins of interest (POIs) by recruiting the ubiquitin-proteasome system, thereby inhibiting the intracellular level of POIs. To date, a variety of small-molecule PROTACs (CRBN, VHL, IAP, and MDM2-based PROTACs) have been developed. IAP-based PROTACs, also known as specific and nongenetic IAP-dependent protein erasers (SNIPERs), are used to degrade the target proteins closely related to diseases. Their structures consist of three parts, including target protein ligand, E3 ligase ligand, and the linker between them. So far, many SNIPERs have been extensively studied worldwide and have performed well in multiple diseases, especially cancer. In this review, we will present the most relevant advances in the field of SNIPERs and provide our perspective on the opportunities and challenges for SNIPERs to become therapeutic agents. [ABSTRACT FROM AUTHOR]

Proteolysis-targeting chimaeras (PROTACs) have been developed to be an emerging technology for targeted protein degradation and attracted the favour of academic institutions, large pharmaceutical enterprises, and biotechnology companies. The mechanism is based on the inhibition of protein function by hijacking a ubiquitin E3 ligase for protein degradation. The heterobifunctional PROTACs contain a ligand for recruiting an E3 ligase, a linker, and another ligand to bind with the protein targeted for degradation. To date, PROTACs targeting ~70 proteins, many of which are clinically validated drug targets, have been successfully developed with several in clinical trials for diseases therapy. In this review, the recent advances in PROTACs against clinically validated drug targets are summarised and the chemical structure, cellular and in vivo activity, pharmacokinetics, and pharmacodynamics of these PROTACs are highlighted. In addition, the potential advantages, challenges, and prospects of PROTACs technology in disease treatment are discussed. [ABSTRACT FROM AUTHOR]

A set of novel diarylpyridines as anti-tubulin agents were designed, synthesised using a rigid pyridine as a linker to fix the cis-orientation of ring-A and ring-B. All of the target compounds were evaluated for their in vitro antiproliferative activities. Among them, 10t showed remarkable antiproliferative activities against three cancer cell lines (HeLa, MCF-7 and SGC-7901) in submicromolar concentrations. Consistent with its potent anti-proliferative activity, 10t also displayed potent anti-tubulin activity. Cellular mechanism investigation elucidated 10t disrupted the cellular microtubule structure, arrested cell cycle at G2/M phase and induces apoptosis. Molecular modelling studies showed that 10t could bind to the colchicine binding site on microtubules. These results provide motivation and further guidance for the development of new CA-4 analogues. [ABSTRACT FROM AUTHOR]

Lipid metabolism appears to play significant roles in the development of cancer. Numerous studies have shown that the evolution of malignancies, including breast, prostate, and colorectal cancers, involves cholesterol in a profound manner. A crucial part in the intestinal absorption of cholesterol is played by Niemann-Pick C1-like 1 (NPC1L1), a cholesterol transporter protein that is widely expressed in the small intestine and liver. The importance of NPC1L1 in tumor prognosis has been demonstrated in investigations in the interim. NPC1L1 also has the potential to develop into a new therapeutic target and a cancer marker. There is, however, no comprehensive review that summarizes NPC1L1's function in cancer. To this end, we outlined NPC1L1's functions in carcinogenesis and treatment, along with resources that can be used to further comprehend the connection between NPC1L1 and tumors. [ABSTRACT FROM AUTHOR]

The hypoxic state of the tumor microenvironment leads to reprogramming lipid metabolism in tumor cells. Adipose triglyceride lipase, also known as patatin-like phospholipase= domain-containing protein 2 and Adipose triglyceride lipase (ATGL), as an essential lipid metabolism-regulating enzyme in cells, is regulated accordingly under hypoxia induction. However, studies revealed that ATGL exhibits both tumor-promoting and tumor-suppressing effects, which depend on the cancer cell type and the site of tumorigenesis. For example, elevated ATGL expression in breast cancer is accompanied by enhanced fatty acid oxidation (FAO), enhancing cancer cells' metastatic ability. In prostate cancer, on the other hand, tumor activity tends to be negatively correlated with ATGL expression. This review outlined the regulation of ATGL-mediated lipid metabolism pathways in tumor cells, emphasizing the Hypoxia-inducible factors 1 (HIF-1)/Hypoxiainducible lipid droplet-associated (HIG-2)/ATGL axis, peroxisome proliferator-activated receptor (PPAR)/G0/G1 switch gene 2 (G0S2)/ATGL axis, and fat-specific protein 27 (FSP-27)/Early growth response protein 1 (EGR-1)/ATGL axis. In the light of recent research on different cancer types, the role of ATGL on tumorigenesis, tumor proliferation, and tumor metastasis was systemically reviewed. [ABSTRACT FROM AUTHOR]