Nagasundaram Nagarajan, Wilson Alphonse Carlton Ranjith, Samuel Gnana Prakash Vincent, Rajaretinam Rajesh Kannan
Molecular and Nanomedicne Research Unit, Centre for Nanoscience and Nanotechnology, Sathyabama University, Jeppiaar Nagar, Chennai 600119, Tamil Nadu, India.
Centre for Marine Science and Technology (CMST), Manonmaniam Sundaranar University, Rajakkamangalam, Kanyakumari District 629502, Tamil Nadu, India.
J Cell Biochem. 2017 Oct;118(10):3462-3471. doi: 10.1002/jcb.26004. Epub 2017 May 18.
Anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC) patients are mostly treated with ALK tyrosine kinase inhibitors (TKIs). Crizotinib is the first generation ALK inhibitor practiced as a primary chemo to combat cancer cells followed by second generation inhibitor ceritinib which are effective against crizotinib resistant ALK mutations. However, patients treated with these drugs invariably relapsed because of the development of new drug resistance mutations. In this study we explored the crizotinib resistance in the presence of ALK mutations L1196M and G1269A through molecular dynamics simulation studies. Further mutation specific inhibitors CID 71748211 and CID 71728095 were identified to potentially inhibit ALK with mutations L1196M and G1269A, respectively. This computational investigation in-sighted the molecular factors involved in crizotinib resistance which enhanced in the identification of new ALK drugs that brings individualized medicine to treat ALK positive NSCLC patients with specific mutations. J. Cell. Biochem. 118: 3462-3471, 2017. © 2017 Wiley Periodicals, Inc.
间变性淋巴瘤激酶（ALK）阳性非小细胞肺癌（NSCLC）患者大多接受ALK酪氨酸激酶抑制剂（TKIs）治疗。克唑替尼是第一代ALK抑制剂，用作主要化疗药物来对抗癌细胞，随后是第二代抑制剂色瑞替尼，它对克唑替尼耐药的ALK突变有效。然而，接受这些药物治疗的患者总是会复发，因为出现了新的耐药突变。在本研究中，我们通过分子动力学模拟研究探索了存在ALK突变L1196M和G1269A时的克唑替尼耐药性。进一步鉴定出了分别对携带L1196M和G1269A突变的ALK有潜在抑制作用的突变特异性抑制剂CID 71748211和CID 71728095。这项计算研究揭示了克唑替尼耐药中涉及的分子因素，这有助于鉴定新的ALK药物，为治疗携带特定突变的ALK阳性NSCLC患者带来个性化医疗。《细胞生物化学杂志》118：3462 - 3471，2017年。©2017威利期刊公司。
