posted on 2018-06-25, 00:00authored byCarlo Baggio, Luca Gambini, Parima Udompholkul, Ahmed F. Salem, Alexander Aronson, Ada Dona, Estelle Troadec, Flavia Pichiorri, Maurizio Pellecchia
Recently
we reported that rapid determination of enthalpy of binding can be
achieved for a large number of congeneric agents or in combinatorial
libraries fairly efficiently. We show that using a thermodynamic Craig
plot can be very useful in dissecting the enthalpy and entropy contribution
of different substituents on a common scaffold, in order to design
potent, selective, or pan-active compounds. In our implementation,
the approach identified a critical Lys residue in the BIR3 domain
of XIAP. We report for the first time that it is possible to target
such residue covalently to attain potent and selective agents. Preliminary
cellular studies in various models of leukemia, multiple myeloma,
and pancreatic cancers suggest that the derived agents possess a potentially
intriguing pattern of activity, especially for cell lines that are
resistant to the pan-IAP antagonist and clinical candidate LCL161.