Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea.
Bioorg Med Chem Lett. 2013 Aug 1;23(15):4324-7. doi: 10.1016/j.bmcl.2013.05.095. Epub 2013 Jun 6.
The existence of drug resistance caused by mutations in the break-point cluster region-Abelson (BCR-ABL) tyrosine kinase domain remains a clinical challenge due to limited treatment options for effective CML therapies. Here, we report a series of flavone-based common inhibitors equipotent for the wild type and the most drug-resistant T315I mutant of BCR-ABL. The original hit 1 was extensively modified through a structure-based drug design strategy, especially by varying the C7 acetamide appendage of the scaffold to exploit extended interactions with P-loop residues. Structural features relevant to the stabilization of the newly identified inhibitors in the ATP-binding site of ABL are discussed in detail.
由于慢性髓细胞白血病（CML）治疗方法有限，BCR-ABL 酪氨酸激酶结构域中突变导致的耐药性仍然是一个临床挑战。在这里，我们报告了一系列基于黄酮类化合物的常见抑制剂，它们对野生型和最耐药的 T315I 突变型 BCR-ABL 均具有等效的抑制作用。原始命中化合物 1 经过基于结构的药物设计策略进行了广泛的修饰，特别是通过改变支架的 C7 乙酰胺侧链，以利用与 P 环残基的扩展相互作用。详细讨论了与新鉴定的抑制剂在 ABL 的 ATP 结合位点中稳定相关的结构特征。
