Small molecule treatment targets lymphoblastic leukemia/lymphoma
Mayo Clinic researchers have developed a small molecule inhibitor of Cyclophilin B (CypB) and PIKfyve kinase for use in treating a variety of cancers, including lymphoblastic leukemia and lymphoma. The endoplasmic reticulum (ER) resident prolyl isomerase Cyclophilin B (CypB) is highly up-regulated in multiple types of cancers. Biochemical analysis revealed that knockdown of CypB enhanced ER stress, and led to elevated reactive oxygen species and decreased levels of Chk1 and mutant p53, as well as decreased activation of Stat3, all of which have been implicated in regulation of cancer cell proliferation, suggesting a mechanism underlying the requirement for CypB in these tumor cells. PIKfyve is an intracellular enzyme that catalyzes the phosphorylation of the 5′ position of phosphatidyl inositol (PI) and of phosphatidyl inositol 3 phosphate (PI3P) to generate PI5P and I3,5P2, respectively. These low abundance lipids regulate multiple vesicular trafficking events that are important for endocytosis, exocytosis, and lysosome function, including macroautophagy. Researchers have identified a novel compound (MC042) that specifically binds and inhibits CypB and PIKfyve in cells for use in cancer treatment.