Current status of drugs targeting PDGF/PDGFR.

As an important proangiogenic factor, platelet-derived growth factor (PDGF) and its receptor PDGFR are highly expressed in a variety of tumors, fibrosis, cardiovascular and neurodegenerative diseases. Targeting the PDGF/PDGFR pathway is therefore a promising therapeutic strategy. At present, a variety of PDGF/PDGFR targeted drugs with potential therapeutic effects have been developed, mainly including PDGF agonists, inhibitors targeting PDGFR and proteolysis targeting chimera (PROTACs). This review clarifies the structure, biological function and disease correlation of PDGF and PDGFR, and it discusses the current status of PDGFR-targeted drugs, so as to provide a reference for subsequent research.

A New Dawn for Targeted Cancer Therapy: Small Molecule Covalent Binding Inhibitor Targeting K-Ras (G12C).

K-Ras is a frequently mutated oncogene in human malignancies, and the development of inhibitors targeting various oncogenic K-Ras mutant proteins is a major challenge in targeted cancer therapy, especially K-Ras(G12C) is the most common mutant, which occurs in pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC), colorectal cancer (CRC) and other highly prevalent malignancies. In recent years, significant progress has been made in developing small molecule covalent inhibitors targeting K-Ras(G12C), thanks to the production of nucleophilic cysteine by the G12C mutant, breaking the "spell" that K-Ras protein cannot be used as a drug target. With the successful launch of sotorasib and adagrasib, the development of small molecule inhibitors targeting various K-Ras mutants has continued to gain momentum. In recent years, with the popularization of highly sensitive surface plasmon resonance (SPR) technology, fragment-based drug design strategies have shown great potential in the development of small molecule inhibitors targeting K-Ras(G12C), but with the increasing number of clinically reported acquired drug resistance, addressing inhibitor resistance has gradually become the focus of this field, indirectly indicating that such small molecule inhibitors still the potential for the development of these small molecule inhibitors are also indirectly indicated. This paper traces the development of small molecule covalent inhibitors targeting K-Ras(G12C), highlighting and analyzing the structural evolution and optimization process of each series of inhibitors and the previous inhibitor design methods and strategies, as well as their common problems and general solutions, in order to provide inspiration and help to the subsequent researchers.

Recent Advances on Natural Aryl-C-glycoside Scaffolds: Structure, Bioactivities, and Synthesis-A Comprehensive Review.

Aryl-C-glycosides, of both synthetic and natural origin, are of great significance in medicinal chemistry owing to their unique structures and stability towards enzymatic and chemical hydrolysis as compared to O-glycosides. They are well-known antibiotics and potent enzyme inhibitors and possess a wide range of biological activities such as anticancer, antioxidant, antiviral, hypoglycemic effects, and so on. Currently, a number of aryl-C-glycoside drugs are on sale for the treatment of diabetes and related complications. This review summarizes the findings on aryl-C-glycoside scaffolds over the past 20 years, concerning new structures (over 200 molecules), their bioactivities-including anticancer, anti-inflammatory, antioxidant, antivirus, glycation inhibitory activities and other pharmacological effects-as well as their synthesis.

A Review on Poly (ADP-ribose) Polymerase (PARP) Inhibitors and Synthetic Methodologies.

Poly (ADP-ribose) polymerase (PARP) acts as an essential DNA repair enzyme. PARP inhibitors are novel small molecule targeted drugs based on the principle of "Synthetic Lethality", which affect DNA repair process by competitively inhibiting the activity of PARP enzyme and thereby kill cancer cells. Currently, four PARP inhibitors including olaparib, rucaparib, niraparib, and talazoparib have been approved by FDA for cancer treatment and have achieved great success in the treatment of ovarian cancer, breast cancer, and pancreatic cancer, etc. This paper provides a general overview of the research progress of PARP inhibitors including the major structure types, structure-activity relationship (SAR), and synthetic routes, with the aim of providing ideas for the discovery and synthesis of novel PARP inhibitors.

Anti-angiogenic Agents: A Review on Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) Inhibitors.

Tumor growth inhibition can be achieved by inhibiting angiogenesis, which has been a field of great concern in recent years. Important targets to inhibit angiogenesis include vascular endothelial growth factor receptor (VEGFR) and its homologous tyrosine kinase receptor. Anti-angiogenic therapy based on inhibition of VEGFR-2 is an effective clinical treatment strategy. The research progress of VEGFR-2 inhibitors is reviewed in this paper from the aspects of drug development and chemical synthesis.

Monoclonal Antibodies, Small Molecule Inhibitors and Antibody-drug Conjugates as HER2 Inhibitors.

Overexpression of human epidermal growth factor receptor (HER)-2 is found in a variety of cancers, often portending poor clinical outcomes. Therefore, HER2 is an attractive target for treatment. This review describes the research progress of HER2 targeted inhibitors in recent years. Excellent reviews are available, so we focus on the development, mechanisms of action, and structure-activity relationships of different types of inhibitors, including monoclonal antibodies, small molecule inhibitors, and antibody-drug conjugates (ADCs). In addition, the differences among them are compared.

"Ring opening-ring closure" strategy for the synthesis of aryl-C-glycosides.

A new "ring-opening-ring closure" strategy for the synthesis of aryl-C-glycosides was described. This strategy exploited the nickel-catalyzed regioselective ß-O elimination of glycals by reactions with various aryl boronic acids or potassium aryltrifluoroborates to yield the ring-opened products, which underwent the Lewis acid, protonic acid, PhSeCl, or NBS mediated ring closure reactions to afford diverse aryl-C-glycosides. After Lewis acids and protonic acids were screened, it was found that, starting from the ring-opened substrates, the Ph3PHBr or Sc(OTf)3 mediated ring closure reaction provided α- or ß-preferred aryl-C-Δ(2,3)-glycosides, respectively. Furthermore, ß-D-phenyl-C-glycosides were successfully prepared via the PhSeCl-mediated cyclization reaction, whereas the α-D-phenyl-C-glycoside was obtained via the NBS-mediated cyclization reaction. After removal of the 2-substituted functionalities by Bu3SnH/AIBN, the synthesis of 2-deoxy-aryl-C-glycosides was ultimately realized in a stereoselective manner.