Even while on current therapies, malaria patients remain infectious for a period of time, allowing further mosquito-borne transmission to others. Control of parasite transmission is critical for elimination and eradication of malaria. However, most antimalarial drugs are not active against sexual stage P. falciparum parasites called gametocytes which are responsible for the spread of malaria from person to person via mosquitoes. To begin to fill this void, investigators screened 5,215 known bioactive compounds and approved drugs for gametocytocidal activity. One compound with favorable pharmacokinetics, Torin2, was selected as the first candidate for further evaluation, including testing in an in vivo rodent malaria transmission model. Two 4 mg/kg doses completely blocked parasites ability to infect mosquitoes, and a 2 mg/kg dose gave a partial blockade, confirming the transmission-blocking activity of Torin2. Preliminary data indicate that the Torin2 target in P. falciparum is distinct from the mammalian target, which means researchers can design malaria-specific derivatives. Investigators used a gametocyte viability assay, a cellular mTOR assay and an in vivo rodent malaria transmission model to identify new malaria-specific Torin2 analogues. The goal of this project is to further optimize the Torin2 series and advance a drug candidate through preclinical development and early clinical development. Pilot studies between the lead collaborator and NCATS scientists resulted in identification of a series of compounds suitable for lead optimization. The TRND team initiated a comprehensive preclinical project plan, performing medicinal chemistry optimization to identify a lead candidate for further development. Initial pharmacology and ADME studies are being performed, with further studies planned to support filing an Investigational New Drug application with the Food and Drug Administration.