In vitro activity: HLCL-61 hydrochloride is a potent, selective, first-in-class small-molecule inhibitor of PRMT5 (protein arginine methyltransferase) that has the potential for treatment of acute myeloid leukemia. HLCL-61 resulted in significantly increased expression of miR-29b and consequent suppression of Sp1 and FLT3 in AML (acute myeloid leukemia) cells. As a result, significant antileukemic activity was achieved. Inhibition of PRMT5 via sh/siRNA or a first-in-class small-molecule inhibitor (HLCL-61) resulted in significantly increased expression of miR-29b and consequent suppression of Sp1 and FLT3 in AML cells. As a result, significant antileukemic activity was achieved. Collectively, the data support a novel leukemogenic mechanism in AML where PRMT5 mediates both silencing and transcription of genes that participate in a 'yin-yang' functional network supporting leukemia growth. As FLT3 is often mutated in AML and pharmacologic inhibition of PRMT5 appears feasible, the PRMT5-miR-29b-FLT3 network should be further explored as a novel therapeutic target for AML.

Kinase Assay: HLCL-61 hydrochloride is a potent, selective, first-in-class small-molecule inhibitor of PRMT5 (protein arginine methyltransferase) that has the potential for treatment of acute myeloid leukemia.

Cell Assay: HLCL-61 resulted in significantly increased expression of miR-29b and consequent suppression of Sp1 and FLT3 in AML (acute myeloid leukemia) cells. As a result, significant antileukemic activity was achieved. Inhibition of PRMT5 via sh/siRNA or a first-in-class small-molecule inhibitor (HLCL-61) resulted in significantly increased expression of miR-29b and consequent suppression of Sp1 and FLT3 in AML cells. As a result, significant antileukemic activity was achieved.