Ferroptosis is an iron-dependent form of oxidative cell death, and the inhibition of ferroptosis is a promising strategy with which to prevent and treat neurological diseases. Herein we report a new ferroptosis inhibitor 9a with a novel mechanism of action. It is demonstrated that nuclear receptor coactivator 4 (NCOA4), a cargo receptor for ferritinophagy, is the target of 9a. Compound 9a blocks ferroptosis by reducing the amount of bioavailable intracellular ferrous iron through disrupting the NCOA4–FTH1 protein–protein interaction. Further studies indicate that 9a directly binds to recombinant protein NCOA4^383–522 and effectively blocks the NCOA4^383–522–FTH1 interaction. In a rat model of ischemic stroke, 9a significantly ameliorates the ischemic-refusion injury. With the first ligand 9a, this work reveals that NCOA4 is a promising drug target. Additionally, 9a is the first NCOA4–FTH1 interaction inhibitor. This work paves a new road to the development of ferroptosis inhibitors against neurological diseases.

Some of the most prominent and promising catalysts in organic synthesis for the requisite construction of C–C and C–N bonds are palladium (Pd) catalysts, which play a pivotal role in pharmaceutical and medicinal chemistry. Their wide range of selectivities, mild reaction conditions, and simple, efficient, and economical protocols make them desirable for the synthesis of highly functionalized molecules, medicinally important intermediates, pharmaceuticals, and agro-products. Researchers from academia and the pharmaceutical industry have also utilized a wide variety of Pd-catalysts for the synthesis of pharmaceuticals on a small and large scale. This review describes pharmaceuticals approved by the United States Food and Drug Administration (the U.S. FDA) between 2015 and 2020, which were synthesized via Pd-catalyzed cross-coupling reactions for the construction of carbon–carbon (C–C) and carbon–nitrogen (C–N) bonds. The review includes both medicinal chemistry routes and patented routes on a bulk scale. Along with details of the synthetic protocols of coupling reactions, the medicinal properties of each approved drug are discussed.

Human Atg4 homologs are cysteine proteases, which play key roles in the macroautophagy/autophagy process by cleaving Atg8 homologs for conjugation to lipid membranes and for deconjugation of Atg8 homologs from membranes. Expression of ATG4B is significantly increased in colorectal cancer cells compared to normal cells, suggesting that ATG4B may be important for cancer biology. Inhibition of ATG4B may reduce the autophagy activity, thereby sensitizing cancer cells to therapeutic agents. Thus, developing specific and potent ATG4B inhibitors for research as well as for potential therapeutic uses is highly needed. In this study, we integrated in silico screening and in vitro assays to discover a potent ATG4B inhibitor, named S130, from a noncommercial library. This chemical binds to ATG4B with strong affinity and specifically suppresses the activity of ATG4B but not other proteases. S130 did not cause the impairment of autophagosome fusion, nor did it result in the dysfunction of lysosomes. Instead, S130 might attenuate the delipidation of LC3-II on the autolysosomes to suppress the recycling of LC3-I, which normally occurs after LC3-II cleavage by ATG4B. Intriguingly, S130 induced cell death, which was accompanied with autophagy stress and could be further exacerbated by nutrient deprivation. Such cytotoxicity could be partially reversed by enhancing ATG4B activity. Finally, we found that S130 was distributed in tumor tissues in vivo and was also effective in arresting the growth of colorectal cancer cells. Thus, this study indicates that ATG4B is a potential anticancer target and S130 might be a novel small-molecule candidate for future cancer therapy.

Covering: up to 2010 After new human transmissible H1N1 (swine flu) viruses were reported in Mexico and the United States in April 2009, the World Health Organization (WHO) announced the emergence of a novel influenza A virus. Most governments in the world have been alerted and are monitoring the situation closely. As one of the official responses to the H1N1 pandemic, the Chinese government has released three editions of a document entitled “Recommended Schemes for Pandemic Influenza A Diagnoses and Treatments”. The third edition recommended the use of not only two targeted anti-flu drugs, oseltamivir and zanamivir, but also four anti-flu TCM (Traditional Chinese Medicine) prescriptions. Since then, TCM has played a significant role in fighting the pandemic. TCM drugs comprise multiple compounds regulating multiple targets for a given class of medical indications, and are tunable to the symptoms of the individual. This review summarizes anti-influenza agents from TCM, including compounds, herbs, and TCM prescriptions, and suggests that, by further investigating TCM theory and mining TCM databases, a better drug discovery paradigm may arise – one that can be beneficial to both TCM and modern medicine.

Biogenic compounds are important materials for drug discovery and chemical biology. In this work, we report a quasi-biogenic molecule generator (QBMG) to compose virtual quasi-biogenic compound libraries by means of gated recurrent unit recurrent neural networks. The library includes stereo-chemical properties, which are crucial features of natural products. QMBG can reproduce the property distribution of the underlying training set, while being able to generate realistic, novel molecules outside of the training set. Furthermore, these compounds are associated with known bioactivities. A focused compound library based on a given chemotype/scaffold can also be generated by this approach combining transfer learning technology. This approach can be used to generate virtual compound libraries for pharmaceutical lead identification and optimization.