SMS121, a new inhibitor of CD36, impairs fatty acid uptake and viability of acute myeloid leukemia.

Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults and the second most common among children. AML is characterized by aberrant proliferation of myeloid blasts in the bone marrow and impaired normal hematopoiesis. Despite the introduction of new drugs and allogeneic bone marrow transplantation, patients have poor overall survival rate with relapse as the major challenge, driving the demand for new therapeutic strategies. AML patients with high expression of the very long/long chain fatty acid transporter CD36 have poorer survival and very long chain fatty acid metabolism is critical for AML cell survival. Here we show that fatty acids are transferred from human primary adipocytes to AML cells upon co-culturing. A drug-like small molecule (SMS121) was identified by receptor-based virtual screening and experimentally demonstrated to target the lipid uptake protein CD36. SMS121 reduced the uptake of fatty acid into AML cells that could be reversed by addition of free fatty acids and caused decreased cell viability. The data presented here serves as a framework for the development of CD36 inhibitors to be used as future therapeutics against AML.

Historical perspective of tumor glycolysis: A century with Otto Warburg.

Tumors have long been known to rewire their metabolism to endorse their proliferation, growth, survival, and invasiveness. One of the common characteristics of these alterations is the enhanced glucose uptake and its subsequent transformation into lactic acid by means of glycolysis, regardless the availability of oxygen or the mitochondria effectiveness. This phenomenon is called the "Warburg effect", which has turned into a century of age now, since its first disclosure by German physiologist Otto Heinrich Warburg. Since then, this peculiar metabolic switch in tumors has been addressed by extensive studies covering several areas of research. In this historical perspective, we aim at illustrating the evolution of these studies over time and their implication in various fields of science.