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Design of Potent pan-IAP and Lys-Covalent XIAP Selective Inhibitors Using a Thermodynamics Driven Approach
Journal of Medicinal Chemistry ( IF 7.3 ) Pub Date : 2018-06-25 00:00:00 , 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
Affiliation  

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.

中文翻译:

使用热力学驱动方法设计有效的pan-IAP和Lys-共价XIAP选择性抑制剂

最近,我们报道了对于大量同类药物或在组合文库中可以相当有效地实现结合焓的快速测定。我们表明,使用热力学克雷格图在剖析通用支架上不同取代基的焓和熵贡献方面非常有用,以设计有效的,选择性的或泛活性的化合物。在我们的实施中,该方法在XIAP的BIR3域中鉴定出关键的Lys残基。我们首次报道,可以共价靶向此类残基以获得有效和选择性的药物。在各种模型的白血病,多发性骨髓瘤和胰腺癌中进行的初步细胞研究表明,衍生药物具有潜在的吸引人的活动模式,
更新日期:2018-06-25
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