KPT-330, A New Candidate Drug for Targeting NOTCH1 Overexpression in T-cell Acute Lymphoblastic Leukemia, An In Vitro and Silico Study.

Abstract

B and T-lymphoid cancers usually originate from lymphoid progenitor cells. T-cell ALL, a subtype of acute lymphoblastic leukemia (ALL), arises due to unlimited and abnormal growth of blast cells. KPT-330, also known as Selinexor, prevents the transport of mRNAs and proteins from the nucleus to the cytoplasm by inhibiting the XPO1 transporter protein. The study aims to explore the NOTCH1 gene as a novel therapeutic target of KPT-330 in T-cell ALL by targeting the XPO1 protein. mRNA expression of the NOTCH1 gene was significantly elevated in T-cell ALL patients. The IC50 value of KPT330 for the Jurkat cells was determined by cell viability assay. The effect of KPT-330 on NOTCH1 gene expression in Jurkat cells was evaluated after 24, 48, and 72 h intervals. KPT-330 significantly downregulated the NOTCH1 gene expression at all time points in a dose-dependent manner. The molecular docking results revealed a binding affinity of -8.8 kcal/mol and identified GLU-140, LEU-141, and SER-144 as the potential amino acids of XPO1 forming a hydrogen bond with KPT-330. In silico analysis suggested the interaction of KPT-330 with the RNA-based NES_1 (UGUAUUAUU), NES_2 (UGUAUUUUU), and NES_3 (UUGUA) motifs in the 3' UTR of NOTCH1 mRNA resulting in NOTCH1 inhibition. Based on the results of in vitro and in silico studies, it was suggested that KPT-330 could be an ideal candidate drug for treating T-cell ALL patients with NOTCH1 overexpression.