Frizzled receptors (FZDs) in Wnt signaling: potential therapeutic targets for human cancers.

Frizzled receptors (FZDs) are key contributors intrinsic to the Wnt signaling pathway, activation of FZDs triggering the Wnt signaling cascade is frequently observed in human tumors and intimately associated with an aggressive carcinoma phenotype. It has been shown that the abnormal expression of FZD receptors contributes to the manifestation of malignant characteristics in human tumors such as enhanced cell proliferation, metastasis, chemotherapy resistance as well as the acquisition of cancer stemness. Given the essential roles of FZD receptors in the Wnt signaling in human tumors, this review aims to consolidate the prevailing knowledge on the specific status of FZD receptors (FZD1-10) and elucidate their respective functions in tumor progression. Furthermore, we delineate the structural basis for binding of FZD and its co-receptors to Wnt, and provide a better theoretical foundation for subsequent studies on related mechanisms. Finally, we describe the existing biological classes of small molecule-based FZD inhibitors in detail in the hope that they can provide useful assistance for design and development of novel drug candidates targeted FZDs.

NSD3: Advances in cancer therapeutic potential and inhibitors research.

Nuclear receptor-binding SET domain 3, otherwise known as NSD3, is a member of the group of lysine methyltransferases and is involved in a variety of cellular processes, including transcriptional regulation, DNA damage repair, non-histone related functions and several others. NSD3 gene is mutated or loss of function in a variety of cancers, including breast, lung, pancreatic, and osteosarcoma. These mutations produce dysfunction of the corresponding tumor tissue proteins, leading to tumorigenesis, progression, chemoresistance, and unfavorable prognosis, which suggests that the development of NSD3 probe molecules is important for understanding the specific role of NSD3 in disease and drug discovery. In recent years, NSD3 has been increasingly reported, demonstrating that this target is a very hot epigenetic target. However, the number of NSD3 inhibitors available for cancer therapy is limited and none of the drugs that target NSD3 are currently available on the market. In addition, there are very few reviews describing NSD3. Within this review, we highlight the role of NSD3 in tumorigenesis and the development of NSD3 targeted small-molecule inhibitors over the last decade. We hope that this publication can serve as a guide for the development of potential drug candidates for various diseases in the field of epigenetics, especially for the NSD3 target.

Recent advances in gout drugs.

Gout is an autoinflammatory disease caused by the deposition of urate crystals. As the most common inflammatory arthritis, gout has a high incidence and can induce various severe complications. At present, there is no effective cure method in the world. With the deepening of medical research, gout treatment drugs continue to progress. In this review, we provide a landscape view of the current state of the research on gout treatment drugs, including the research progress of anti-inflammatory and analgesic drugs, drugs that promote uric acid excretion, and drugs that inhibit uric acid production. We mainly emphasize the understanding of gout as an auto-inflammatory disease and the discovery strategy of related gout drugs to provide a systematic and theoretical basis for the new exploration of gout drug discovery.

Inhibitors of SARS-CoV-2 Entry: Current and Future Opportunities.

Recently, a novel coronavirus initially designated 2019-nCoV but now termed SARS-CoV-2 has emerged and raised global concerns due to its virulence. SARS-CoV-2 is the etiological agent of "coronavirus disease 2019", abbreviated to COVID-19, which despite only being identified at the very end of 2019, has now been classified as a pandemic by the World Health Organization (WHO). At this time, no specific prophylactic or postexposure therapy for COVID-19 are currently available. Viral entry is the first step in the SARS-CoV-2 lifecycle and is mediated by the trimeric spike protein. Being the first stage in infection, entry of SARS-CoV-2 into host cells is an extremely attractive therapeutic intervention point. Within this review, we highlight therapeutic intervention strategies for anti-SARS-CoV, MERS-CoV, and other coronaviruses and speculate upon future directions for SARS-CoV-2 entry inhibitor designs.

Discovery of novel 1,2,3-triazole oseltamivir derivatives as potent influenza neuraminidase inhibitors targeting the 430-cavity.

A novel series of 1,2,3-triazole oseltamivir derivatives, which could simultaneously occupy the classical NA catalytic site and the newly reported 430-cavity, were designed, synthesized, and evaluated for their anti-influenza activities. The results demonstrated that four compounds (6g, 6l, 6y and 8c) showed robust anti-influenza potencies against H5N1, H5N2 and H5N6 strains in both enzymatic assay and cellular assay. Especially, 6l was proved to possess the most potent and broad-spectrum anti-influenza activity, with IC50 values of 0.12 µM, 0.049 µM and 0.16 µM and EC50 values of 2.45 µM, 0.43 µM and 2.8 µM against H5N1, H5N2 and H5N6 strains, respectively, which were slightly weaker than oseltamivir carboxylate. In addition, in the embryonated egg model, 6l achieved the similar protective effect against H9N2 strain with oseltamivir carboxylate in the tested concentrations. Preliminary structure-activity relationships (SARs), molecular modeling, and calculated physicochemical properties of selected compounds were also discussed.