Fernández Ariel, Sanguino Angela, Peng Zhenghong, Crespo Alejandro, Ozturk Eylem, Zhang Xi, Wang Shimei, Bornmann William, Lopez-Berestein Gabriel
Department of Bioengineering, Rice University, Houston, TX 77005, USA.
Cancer Res. 2007 May 1;67(9):4028-33. doi: 10.1158/0008-5472.CAN-07-0345.
Protein kinases are central targets for drug-based cancer treatment. To avoid functional impairment, the cell develops mechanisms of drug resistance, primarily based on adaptive mutations. Redesigning a drug to target a drug-resistant mutant kinase constitutes a therapeutic challenge. We approach the problem by redesigning the anticancer drug imatinib guided by local changes in interfacial de-wetting propensities of the C-Kit kinase target introduced by an imatinib-resistant mutation. The ligand is redesigned by sculpting the shifting hydration patterns of the target. The association with the modified ligand overcomes the mutation-driven destabilization of the induced fit. Consequently, the redesigned drug inhibits both mutant and wild-type kinase. The modeling effort is validated through molecular dynamics, test tube kinetic assays of downstream phosphorylation activity, high-throughput bacteriophage-display kinase screening, cellular proliferation assays, and cellular immunoblots. The inhibitor redesign reported delineates a molecular engineering paradigm to impair routes for drug resistance.
蛋白激酶是基于药物的癌症治疗的核心靶点。为避免功能受损，细胞主要通过适应性突变形成耐药机制。重新设计药物以靶向耐药突变激酶构成了一项治疗挑战。我们通过在伊马替尼耐药突变引入的C-Kit激酶靶点的界面去湿倾向的局部变化的指导下重新设计抗癌药物伊马替尼来解决这个问题。通过塑造靶点不断变化的水合模式来重新设计配体。与修饰配体的结合克服了突变驱动的诱导契合的不稳定。因此，重新设计的药物既能抑制突变型激酶，也能抑制野生型激酶。通过分子动力学、下游磷酸化活性的试管动力学测定、高通量噬菌体展示激酶筛选、细胞增殖测定和细胞免疫印迹对建模工作进行了验证。所报道的抑制剂重新设计描绘了一种损害耐药途径的分子工程范例。
