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Combating Drug-Resistant Mutants of Anaplastic Lymphoma Kinase with Potent and Selective Type-I1/2 Inhibitors by Stabilizing Unique DFG-Shifted Loop Conformation
ACS Central Science ( IF 12.7 ) Pub Date : 2017-11-03 00:00:00 , DOI: 10.1021/acscentsci.7b00419 Peichen Pan , Huidong Yu 1 , Qinglan Liu 2, 3 , Xiaotian Kong , Hu Chen 2 , Jiean Chen 2 , Qi Liu 2 , Dan Li , Yu Kang , Huiyong Sun , Wenfang Zhou , Sheng Tian , Sunliang Cui , Feng Zhu , Youyong Li , Yong Huang 2 , Tingjun Hou
ACS Central Science ( IF 12.7 ) Pub Date : 2017-11-03 00:00:00 , DOI: 10.1021/acscentsci.7b00419 Peichen Pan , Huidong Yu 1 , Qinglan Liu 2, 3 , Xiaotian Kong , Hu Chen 2 , Jiean Chen 2 , Qi Liu 2 , Dan Li , Yu Kang , Huiyong Sun , Wenfang Zhou , Sheng Tian , Sunliang Cui , Feng Zhu , Youyong Li , Yong Huang 2 , Tingjun Hou
Affiliation
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Targeted inhibition of anaplastic lymphoma kinase (ALK) dramatically improved therapeutic outcomes in the treatment of ALK-positive cancers, but unfortunately patients invariably progressed due to acquired resistance mutations in ALK. Currently available drugs are all type-I inhibitors bound to the ATP-binding pocket and are most likely to be resistant in patients harboring genetic mutations surrounding the ATP pocket. To overcome drug resistance, we rationally designed a novel kind of “bridge” inhibitor, which specially bind into an extended hydrophobic back pocket adjacent to the ATP-binding site of ALK. The novel type-I1/2 inhibitors display excellent antiproliferation activity against ALK-positive cancer cells and appear superior to two clinically used drugs, crizotinib and ceritinib. Structural and molecular modeling analyses indicate that the inhibitor induces dramatic conformational transition and stabilizes unique DFG-shifted loop conformation, enabling persistent sensitivity to different genetic mutations in ALK. These data highlight a rationale for further development of next-generation ALK inhibitors to combat drug resistance.
中文翻译：
通过稳定独特的DFG移位环构型与高效和选择性I1 / 2抑制剂对抗间变性淋巴瘤激酶的抗药性突变体。
靶向抑制间变性淋巴瘤激酶（ALK）可以显着改善ALK阳性癌症的治疗效果，但是不幸的是，由于ALK的获得性耐药突变，患者总是进展。当前可用的药物都是与ATP结合袋结合的所有I型抑制剂，最有可能对在ATP袋周围具有基因突变的患者产生抗药性。为了克服耐药性，我们合理地设计了一种新型的“桥”抑制剂，该抑制剂专门结合到ALK ATP结合位点附近的扩展疏水后袋中。新型I-1 / 2抑制剂对ALK阳性癌细胞显示出优异的抗增殖活性，并且优于两种临床使用的药物克唑替尼和塞立替尼。结构和分子建模分析表明，该抑制剂诱导了显着的构象转变并稳定了独特的DFG移位的环构象，从而使人们对ALK中的不同基因突变具有持久的敏感性。这些数据凸显了进一步开发下一代ALK抑制剂以抗药性的基本原理。
更新日期：2017-11-22
中文翻译：
通过稳定独特的DFG移位环构型与高效和选择性I1 / 2抑制剂对抗间变性淋巴瘤激酶的抗药性突变体。
靶向抑制间变性淋巴瘤激酶（ALK）可以显着改善ALK阳性癌症的治疗效果，但是不幸的是，由于ALK的获得性耐药突变，患者总是进展。当前可用的药物都是与ATP结合袋结合的所有I型抑制剂，最有可能对在ATP袋周围具有基因突变的患者产生抗药性。为了克服耐药性，我们合理地设计了一种新型的“桥”抑制剂，该抑制剂专门结合到ALK ATP结合位点附近的扩展疏水后袋中。新型I-1 / 2抑制剂对ALK阳性癌细胞显示出优异的抗增殖活性，并且优于两种临床使用的药物克唑替尼和塞立替尼。结构和分子建模分析表明，该抑制剂诱导了显着的构象转变并稳定了独特的DFG移位的环构象，从而使人们对ALK中的不同基因突变具有持久的敏感性。这些数据凸显了进一步开发下一代ALK抑制剂以抗药性的基本原理。
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