The central role of dysregulated kinase activity in the etiology of progressive disorders, including cancer, has fostered incremental efforts on drug discovery programs over the past 40 years. As a result, kinase inhibitors are today one of the most important classes of drugs. The FDA approved 73 small molecule kinase inhibitor drugs until September 2021, and additional inhibitors were approved by other regulatory agencies during that time. To complement the published literature on clinical kinase inhibitors, we have prepared a review that recaps this large data set into an accessible format for the medicinal chemistry community. Along with the therapeutic and pharmacological properties of each kinase inhibitor approved across the world until 2020, we provide the synthesis routes originally used during the discovery phase, many of which were only available in patent applications. In the last section, we also provide an update on kinase inhibitor drugs approved in 2021.

Cellular senescence is a stress response involved in ageing and diverse disease processes including cancer, type-2 diabetes, osteoarthritis and viral infection. Despite growing interest in targeted elimination of senescent cells, only few senolytics are known due to the lack of well-characterised molecular targets. Here, we report the discovery of three senolytics using cost-effective machine learning algorithms trained solely on published data. We computationally screened various chemical libraries and validated the senolytic action of ginkgetin, periplocin and oleandrin in human cell lines under various modalities of senescence. The compounds have potency comparable to known senolytics, and we show that oleandrin has improved potency over its target as compared to best-in-class alternatives. Our approach led to several hundred-fold reduction in drug screening costs and demonstrates that artificial intelligence can take maximum advantage of small and heterogeneous drug screening data, paving the way for new open science approaches to early-stage drug discovery.

Selective activation of chemotherapeutics at the tumor site via bioorthogonal catalysis is a promising strategy to reduce collateral damage to healthy tissues and organs. Despite significant advances in this field, targeted drug activation by transition-metal catalysts is still limited by insufficient spatiotemporal control over the metal-mediated uncaging process. Herein, we report the development of anisotropic Pd@Au plasmonic nanorods with the capacity to accelerate dealkylation reactions under near-infrared (NIR) irradiation, thereby enabling precise control over when and where these catalytic devices are switched on. We also show that the stability and in cellulo chemical properties of Pd@Au nanorods are enhanced by Au-S functionalization with PEGylated phospholipids and report the development of a novel masking group for prodyes and prodrugs: the POxOC group, designed to improve physicochemical properties and the rate of the Pd-triggered dye/drug release process. NIR-photoactivation of lipo-Pd@Au nanorods is able to catalyze the uncaging of inactive drug precursors and release heat to the environment, killing cancer cells in culture and xenografted in zebrafish. This work provides a novel targeted strategy for photothermal chemotherapy by NIR-laser focalization.

Malaria and Chagas disease, caused by Plasmodium spp. and Trypanosoma cruzi parasites, remain important global health problems. Available treatments for those diseases present several limitations, such as lack of efficacy, toxic side effects, and drug resistance. Thus, new drugs are urgently needed. The discovery of new drugs may be benefited by considering the significant biological differences between hosts and parasites. One of the most striking differences is found in the purine metabolism, because most of the parasites are incapable of de novo purine biosynthesis. Herein, we have analyzed the in vitro anti-P. falciparum and anti-T. cruzi activity of a collection of 81 purine derivatives and pyrimidine analogs. We firstly used a primary screening at three fixed concentrations (100, 10, and 1 µM) and progressed those compounds that kept the growth of the parasites < 30% at 100 µM to dose–response assays. Then, we performed two different cytotoxicity assays on Vero cells and human HepG2 cells. Finally, compounds specifically active against T. cruzi were tested against intracellular amastigote forms. Purines 33 (IC₅₀ = 19.19 µM) and 76 (IC₅₀ = 18.27 µM) were the most potent against P. falciparum. On the other hand, 6D (IC₅₀ = 3.78 µM) and 34 (IC₅₀ = 4.24 µM) were identified as hit purines against T. cruzi amastigotes. Moreover, an in silico docking study revealed that P. falciparum and T. cruzi hypoxanthine guanine phosphoribosyltransferase enzymes could be the potential targets of those compounds. Our study identified two novel, purine-based chemotypes that could be further optimized to generate potent and diversified anti-parasitic drugs against both parasites.