Synergistic AML Cell Death Induction by Marine Cytotoxin (+)-1( R ), 6( S ), 1'( R ), 6'( S ), 11( R ), 17( S )-Fistularin-3 and Bcl-2 Inhibitor Venetoclax.

Treatment of acute myeloid leukemia (AML) patients is still hindered by resistance and relapse, resulting in an overall poor survival rate. Recently, combining specific B-cell lymphoma (Bcl)-2 inhibitors with compounds downregulating myeloid cell leukemia (Mcl)-1 has been proposed as a new effective strategy to eradicate resistant AML cells. We show here that 1( R ), 6( S ), 1'( R ), 6'( S ), 11( R ), 17( S )-fistularin-3, a bromotyrosine compound of the fistularin family, isolated from the marine sponge Suberea clavata , synergizes with Bcl-2 inhibitor ABT-199 to efficiently kill Mcl-1/Bcl-2-positive AML cell lines, associated with Mcl-1 downregulation and endoplasmic reticulum stress induction. The absolute configuration of carbons 11 and 17 of the fistularin-3 stereoisomer was fully resolved in this study for the first time, showing that the fistularin we isolated from the marine sponge Subarea clavata is in fact the (+)-11( R ), 17( S )-fistularin-3 stereoisomer keeping the known configuration 1( R ), 6( S ), 1'( R ), and 6'( S ) for the verongidoic acid part. Docking studies and in vitro assays confirm the potential of this family of molecules to inhibit DNA methyltransferase 1 activity.