摘要
背景:表皮生长因子受体(EGFR)是被广泛认可的用于治疗非小细胞肺癌(NSCLC)的药物靶点。吉非替尼和厄洛替尼是用于EGFR激活突变体的第一代临床应用的抑制剂。然而,在治疗过程中,这些抑制剂由于获得性二级突变的出现而变得无效。随后,为了克服非反应性,第二代和第三代抑制剂被设计为具有共价键和不可逆的作用模式。然而,这些抑制剂被证明是有毒的。这导致了具有完全不同的作用方式和治疗功效的潜在候选人的发现。 目的:我们已经回顾了研究人员最近在发现新的非共价可逆下一代抑制剂治疗NSCLC方面所做的努力。 方法:我们首先研究了合成分子的优化步骤和药代动力学变量。我们还使用PDB X射线晶体结构分析了键和相互作用,并进行了支架和选择性分析。 结果:我们发现配体亲脂效率驱动效能是维持分子药物可能性的优选参数。此外,很少有h债券被认定为影响化合物结合的主要参与者。支架分析显示,具有嘧啶核心的配体分子对TMLR表现出较高的抑制活性,以及相对于其它激酶的较高选择性。 结论:下一代可逆抑制剂显示出独特的结合模式,并被发现占据三个主要口袋(核糖袋,后袋和铰链区),这对于提高化合物对TMLR突变体的选择性至关重要。
关键词: EGFR,可逆抑制剂,共价抑制剂,激活突变,次级突变体,TMLR抑制剂
图形摘要
Current Cancer Drug Targets
Title:Insight into Discovery of Next Generation Reversible TMLR Inhibitors Targeting EGFR Activating and Drug Resistant T790M Mutants
Volume: 17 Issue: 7
关键词: EGFR,可逆抑制剂,共价抑制剂,激活突变,次级突变体,TMLR抑制剂
摘要: Background: Epidermal growth factor receptor (EGFR) is a well-recognised drug target exploited for treating non-small cell lung cancer (NSCLC). Gefitinib and erlotinib are first generation clinically employed inhibitors used against EGFR activating mutants. However, during course of treatment these inhibitors become ineffective due to the emergence of an acquired secondary mutation. Subsequently, in order to overcome non-responsiveness second and third generation inhibitors were designed having covalent bond and irreversible mode of action. However, these inhibitors were shown to be toxic. This led to the discovery of lead candidates with completely different mode of action and therapeutic efficacy.
Objective: We have reviewed the recent efforts undertaken by researchers in discovering newer noncovalent reversible next generation inhibitors for treating NSCLC. Methods: We first studied the optimization steps and pharmacokinetic variables of the synthesised molecules. We also analysed bonds and interactions using PDB X-ray crystal structures as well as scaffold and selectivity analysis was undertaken. Results: We identified that ligand lipophilic efficiency driven potency is a preferable optimisation parameter for maintaining drug likeliness of the molecule. Also, few h-bonds were recognised as major players in affecting the binding of compound. The scaffold analysis revealed that ligand molecules with pyrimidine core exhibit higher inhibitory activity against TMLR, as well as higher selectivity with respect to other kinases. Conclusion: Next generation reversible inhibitors exhibited unique binding mode and were found to occupy three major pockets (ribose pocket, back pocket and hinge region), which is critical for increasing the selectivity of the compound against TMLR mutants.Export Options
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Cite this article as:
Insight into Discovery of Next Generation Reversible TMLR Inhibitors Targeting EGFR Activating and Drug Resistant T790M Mutants, Current Cancer Drug Targets 2017; 17 (7) . https://dx.doi.org/10.2174/1568009617666170330112842
DOI https://dx.doi.org/10.2174/1568009617666170330112842 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
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