Abstract 1568 Identification of new small-molecule CD36 antagonists

CD36 is highly expressed in diverse cancer cells, where it increases fatty acid uptake, reprogramming lipid metabolism. Furthermore, CD36+ cancer cells display increased stemness and functional properties associated to malignancy, including clonogenicity, chemo- and radioresistance, and metastasis-initiating capability. Thus, CD36 has been pointed as a potential therapeutic target in cancer. Here, we searched for druggable pockets in CD36 and performed a virtual screening from a chemical library of drug-like compounds by molecular docking and molecular dynamics. The activity of selected compounds as CD36 antagonists was assessed in HEPG2 cells. Transport of fluorescent palmitic acid (PA) was measured by flow cytometry and clonogenicity was evaluated in tumorsphere assays. We identified a pocket within the fatty acid channel of CD36 that: i) is druggable; ii) includes key functional residues; iii) contains "hot spots" for the binding of small molecules; and iv) is likely the binding site for reported CD36 inhibitors. We docked +25,000 compounds into the identified pocket using three different software and selected fifteen potential antagonists that bind CD36 with high ligand efficiency independently of the method employed. Selection refinement by molecular dynamics pinpointed four compounds that were purchased for in vitro biological evaluation. Three out of the four compounds inhibited PA transport and reduced the sphere-promoting effect of PA. These bioactive compounds can become lead compound for the development of CD36-targeting therapies. Supported by CONAHCYT A1-S-18285 and PAPIIT-UNAM grant numbers IV200121 and IN206622