Proteolysis of platelet-bound GARP by thrombin liberates active TGF-β and contributes to cancer immune evasion in the tumor microenvironment.

Cancer is the second most common cause of death in the United States, accounting for 602,350 deaths in 2020. Cancer-related death rates have declined by 27% over the past two decades, partially due to the identification of novel anti-cancer drugs. Despite improvements in cancer treatment, newly approved oncology drugs are associated with increased toxicity risk. These toxicities may be mitigated by pharmacokinetic optimization and reductions in off-target interactions. As such, there is a need for early-stage implementation of pharmacokinetic (PK) prediction tools. Several PK prediction platforms exist, including pkCSM, SuperCypsPred, Pred-hERG, Similarity Ensemble Approach (SEA), and SwissADME. These tools can be used in screening hits, allowing for the selection of compounds were reduced toxicity and/or risk of attrition. In this short commentary, we used PK prediction tools in the optimization of mitogen activated extracellular signal-related kinase kinase 1 (MEK1) inhibitors. In doing so, we identified MEK1 inhibitors with retained activity and optimized predictive PK properties, devoid of hERG inhibition. These data support the use of publicly available PK prediction platforms in early-stage drug discovery to design safer drugs.

Small molecule inhibitors of CD38 promote increases in interferon gamma and stimulate natural killer cell proliferation for the treatment of neuroblastoma.

Malaria elimination requires multipronged approaches, including the application of antimalarial drugs able to block human‐to‐mosquito transmission of malaria parasites. The transmissible gametocytes of Plasmodium falciparum seem to be highly sensitive towards epidrugs, particularly those targeting demethylation of histone post‐translational marks. Here, we report exploration of compounds from a chemical library generated during hit‐to‐lead optimization of inhibitors of the human histone lysine demethylase, KDM4B. Derivatives of 2‐([1,1′‐biphenyl]‐4‐carboxamido) benzoic acid, around either the amide or a sulfonamide linker backbone (2‐(arylcarboxamido)benzoic acid, 2‐carboxamide (arylsulfonamido)benzoic acid and N‐(2‐(1H‐tetrazol‐5‐yl)phenyl)‐arylcarboxamide), showed potent activity towards late‐stage gametocytes (stage IV/V) of P. falciparum, with the most potent compound reaching single digit nanomolar activity. Structure‐activity relationship trends were evident and frontrunner compounds also displayed microsomal stability and favourable solubility profiles. Simplified synthetic routes support further derivatization of these compounds for further development of these series as malaria transmission‐blocking agents.

With the advent of checkpoint inhibitors (CI), immunotherapies have revolutionized the field of oncology and the ways in which malignancies are treated. Many of the CIs on the market today function by preventing the ligation of immunosuppressive receptors on a subset of lymphocytes known as T cells. As such, T cells that infiltrate the tumor microenvironment (TME) are able to