Preclinical investigation of LP-118, a dual BCL-2 and BCL-XL inhibitor, in acute myeloid leukemia

Abstract

Acute myeloid leukemia (AML) is a malignancy of myeloid lineage hematopoietic cells. Overexpression of the protein BCL-2 often prevents apoptosis, but dependency on BCL-2 for survival can be targeted using venetoclax, a selective small-molecule inhibitor of BCL-2. Relapsed or refractory AML can be dependent on BCL-XL or MCL-1 for survival, which causes venetoclax resistance. Here, we describe the preclinical investigation of LP-118, a small-molecule BCL-2 and BCL-XL inhibitor. LP-118 induces cell death at lower concentrations than venetoclax in AML cell lines, and dependence on BCL-XL tends to predict sensitivity to LP-118 and resistance to venetoclax. Moreover, LP-118 prolongs survival in a cell line derived xenograft mouse model of AML, and inhibition of CDK4/6 alongside LP-118 causes synergistic cell death in an AML cell line. Altogether, LP-118 displays promising preclinical characteristics that may sensitize AML dependent on BCL-XL for survival to cell death, presenting a potential improved therapeutic modality in AML.Pelotonia ScholarshipA three-year embargo was granted for this item.Academic Major: Biomedical Scienc