Synthesis, structure-activity relationships, antitumor activities and mechanistic studies of ENL-degrading compounds.

Transcription cofactor ENL is a novel target for MLL-rearranged (MLL-r) leukemia and other blood cancers. We designed and synthesized several series of ENL-degrading compounds. Cereblon-recruiting, proteolysis targeting chimera (PROTAC) compounds 1-6 and 14 can efficiently degrade and deplete ENL with DC50 as low as 4.2 nM, but not its paralog AF9. Mechanistic studies showed that the lysine residues of ENL(173-190) are critical for selective ENL degradation. These compounds selectively inhibited proliferation of MLL-r leukemia and multiple myeloma cells with EC50s as low as 130 nM. Depletion of ENL mimicked ENL-knockdown and significantly suppressed expression of MYC and its target genes, causing inhibited cell proliferation. Combination treatment with a BRD4 inhibitor was synergistic. Compound 14 underwent rapid metabolic degradations when exposed to human microsomes. More medicinal chemistry optimization is therefore needed in the perspective of drug discovery targeting MLL-r leukemia and other blood cancers.