1. Academic Validation
  2. Design of Potent pan-IAP and Lys-Covalent XIAP Selective Inhibitors Using a Thermodynamics Driven Approach

Design of Potent pan-IAP and Lys-Covalent XIAP Selective Inhibitors Using a Thermodynamics Driven Approach

  • J Med Chem. 2018 Jul 26;61(14):6350-6363. doi: 10.1021/acs.jmedchem.8b00810.
Carlo Baggio 1 Luca Gambini 1 Parima Udompholkul 1 Ahmed F Salem 1 Alexander Aronson 1 Ada Dona 2 Estelle Troadec 2 Flavia Pichiorri 2 Maurizio Pellecchia 1
Affiliations

Affiliations

  • 1 Division of Biomedical Sciences, School of Medicine , University of California Riverside , 900 University Avenue , Riverside , California 92521 , United States.
  • 2 Department of Hematologic Malignancies Translational Science , City of Hope, BioMedical Research Center , Monrovia , California 91016 , United States.
Abstract

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.

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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-15518
    99.91%, IAP Inhibitor
    IAP