Lysine Covalent Antagonists of Melanoma Inhibitors of Apoptosis Protein

We have recently reported on Lys-covalent
agents that, based on
aryl-sulfonyl fluorides, were designed to target binding site Lys
311 in the X-linked inhibitor of apoptosis protein (XIAP). Similar
to XIAP, melanoma-IAP (ML-IAP), a less well-characterized IAP family
protein, also presents a lysine residue (Lys 135), which is in a position
equivalent to that of Lys 311 of XIAP. On the contrary, two other
members of the IAP family, namely, cellular-IAPs (cIAP1 and cIAP2),
present a glutamic acid residue in that position. Hence, in the present
work, we describe the derivation and characterization of the very
first potent ML-IAP Lys-covalent inhibitor with cellular activity.
The agent can be used as a pharmacological tool to further validate
ML-IAP as a drug target and eventually for the development of ML-IAP-targeted
therapeutics.