Conference Agenda

The rapid emergence of drug‑resistant Plasmodium falciparum necessitates novel antimalarial strategies. Because parasite survival relies on extensive modification of host erythrocytes, host‑directed therapies represent an attractive approach. Here, we evaluated a panel of anticancer kinase inhibitors as potential antimalarials, initially hypothesising that they act through inhibition of host signalling pathways. We focused on the proposed requirement for activation of the human MAPK pathway in infected erythrocytes for parasite proliferation. The MAPK pathway tightly regulates cellular proliferation and survival, and its dysregulation in cancer has driven the development of numerous selective kinase inhibitors. Several compounds, displayed submicromolar potency against both asexual erythrocytic‑stage parasites and sexual gametocytes, indicating potential for dual curative and transmission‑blocking efficacy. However, detailed mechanistic studies of MEK1 inhibitors provided little evidence for host‑directed activity. Overexpression of human MEK1 in infected erythrocytes did not alter drug potency, parasites exposed continuously to one MEK1 inhibitor rapidly evolved resistance, and another inhibitor exhibited marked strain‑dependent activity across P. falciparum isolates. These observations support a parasite‑directed mode of action. Collectively, our findings demonstrate that human MEK1 is not essential for parasite proliferation. Despite host toxicity, parasite‑selective activity provides a platform for designing kinase inhibitor derivatives.