A Novel Compound, LG-362B, Inhibits The Development Of Acute Promyelocvtic Leukemia Through Targeting PML-RARα Complex

Leukemia is a kind of malignant hematologic cancer. It has a high lethality as a great threat to patients’health. Acute Myeloid Leukemia(AML) is one of the most common leukemia with higher incidence on the old and children. Many effective clinical agents have been developed for molecular targeted cancer therapy. Acute Promyelocytic Leukemia (APL) is an example for targeted therapeutic drugs discovery even though AML has been divided into different subtypes. ATRA and ATO have been the classical agents for APL through targeting PML-RARa complex with much side effects and resistance. In order to lessen the induciable symptoms and resistance, we discovered a novel effective compound, LG-362B, selectively and significantly induced apoptosis and inhibited aberrant proliferation of Acute Promyelocytic Leukemia (APL) in vitro and in vivo. Considering that all-trans retinoic acid (ATRA) completely revolutionized the management of APL in clinic through differentiation induction, I tested its ability to induce differentiation of promyelocytes and illustrated that it was capable to relieve differentiation arrest morphologically and molecularly, suggesting that it was potential to be an agent participated in both differentiation and classical cytotoxicity. To cover the shortage of ATRA resistance in clinic, I demonstrated LG362-B’s efficacy on ATRA-resistant APL cells and transplantable ATRA-resistant APL mouse models. Given this positive hit, I further illustrated that the downregulation of PML-RARa complex, the potential APL target, in caspases-dependent manner when treated with LG-362B, but the mRNA level is not affected, this is a good explanation for LG-362B’s specific sensitivity and anti-ATRA resistance.