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

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.此前我们曾报道，可高效快速地测定大量同系化合物或组合库的结合焓。我们发现，借助热力学克雷格图（Thermodynamic Craig Plot），可有效解析常见母核上不同取代基的焓与熵贡献，进而设计强效、选择性或泛活性化合物。在本研究的应用中，该方法成功识别出XIAP的BIR3结构域内一个关键赖氨酸残基。我们首次报道了可通过共价靶向该残基以获得强效且具有选择性的活性物质。针对白血病、多发性骨髓瘤及胰腺癌的多种模型开展的初步细胞实验表明，所获得的活性物质具备颇具潜力的活性特征，尤其对泛IAP拮抗剂及临床候选药物LCL161产生耐药性的细胞系效果突出。