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Insight into the Therapeutic Selectivity of the Irreversible EGFR Tyrosine Kinase Inhibitor Osimertinib through Enzyme Kinetic Studies
Biochemistry ( IF 2.9 ) Pub Date : 2020-03-31 , DOI: 10.1021/acs.biochem.0c00104 Xiang Zhai 1 , Richard A. Ward 2 , Peter Doig 1 , Argyrides Argyrou 3
Biochemistry ( IF 2.9 ) Pub Date : 2020-03-31 , DOI: 10.1021/acs.biochem.0c00104 Xiang Zhai 1 , Richard A. Ward 2 , Peter Doig 1 , Argyrides Argyrou 3
Affiliation
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Osimertinib is a covalent, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) approved for treating non-small cell lung cancer patients with activating EGFR mutations (Exon19del or L858R) or with the T790M resistance mutation following disease progression on first- or second-generation EGFR TKIs. The aim of this work is to rationalize and understand how osimertinib achieves mutant EGFR selectivity over the wild-type (WT) by evaluating its kinetic mechanism of action. In doing so, we developed methodologies combining steady-state and pre-steady-state kinetics to determine the covalent inactivation rates (kinact) and reversible binding affinities (Ki) for osimertinib against WT, L858R, and L858R/T790M EGFR and compared these data to the inhibition kinetics of earlier generations of EGFR TKIs. The kinact/KI values indicate osimertinib inactivates L858R and L858R/T790M with 20- and 50-fold higher overall efficiencies, respectively, compared to that for WT. The Ki and kinact values reveal that osimertinib binds 3-fold tighter to and reacts 3-fold faster with L858R than WT EGFR and binds 17-fold tighter to and reacts 3-fold faster with L858R/T790M than with the WT EGFR. We conclude that osimertinib overcomes the T790M mutation through improved affinities from stronger hydrophobic interactions with Met790 versus Thr790 and an improved rate of covalent bond formation via better positioning of the acrylamide warhead, while osimertinib targets the L858R mutation through better affinities and reactivities with the mutant in the context of differential binding affinities of the competing substrate ATP. This work highlights the importance of optimizing both reversible drug–target interactions and inactivation rates for covalent inhibitors to achieve selectivity in targeting mutant EGFRs.
中文翻译：
通过酶动力学研究洞悉不可逆的EGFR酪氨酸激酶抑制剂Osimertinib的治疗选择性
Osimertinib是一种共价的第三代表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI），已批准用于治疗具有激活EGFR突变（Exon19del或L858R）或在疾病进展后具有T790M抗性突变的非小细胞肺癌患者。第一代或第二代EGFR TKI。这项工作的目的是通过评估其动力学机制来合理化和了解奥西替尼如何实现对野生型（WT）的突变EGFR选择性。为此，我们开发了结合稳态和稳态前动力学的方法，以确定共价灭活率（k inact）和可逆结合亲和力（K i）用于针对WT，L858R和L858R / T790M EGFR的奥西替尼，并将这些数据与早期EGFR TKIs的抑制动力学进行了比较。所述ķ INACT / ķ余数值表示osimertinib使其失活L858R和L858R / T790M与20-和50倍高的总效率，分别相比于WT供。的ķ我和ķ INACT值显示，奥西替尼与L858R的结合力比WT EGFR高3倍，与L858R的反应快3倍，与L858R / T790M相比，与WEGFR的结合更紧密17倍，反应快3倍。我们得出的结论是，奥西替尼通过与Met790相对于Thr790的更强的疏水性相互作用改善了亲和力，克服了T790M突变，并且通过更好地定位丙烯酰胺弹头提高了共价键形成速率，而奥西替尼通过与突变体更好的亲和力和反应性靶向L858R突变。竞争底物ATP的差异结合亲和力的背景。这项工作强调了优化可共价抑制剂的可逆药物-靶标相互作用和失活率以实现靶向突变EGFRs的选择性的重要性。
更新日期：2020-04-01
中文翻译：
通过酶动力学研究洞悉不可逆的EGFR酪氨酸激酶抑制剂Osimertinib的治疗选择性
Osimertinib是一种共价的第三代表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI），已批准用于治疗具有激活EGFR突变（Exon19del或L858R）或在疾病进展后具有T790M抗性突变的非小细胞肺癌患者。第一代或第二代EGFR TKI。这项工作的目的是通过评估其动力学机制来合理化和了解奥西替尼如何实现对野生型（WT）的突变EGFR选择性。为此，我们开发了结合稳态和稳态前动力学的方法，以确定共价灭活率（k inact）和可逆结合亲和力（K i）用于针对WT，L858R和L858R / T790M EGFR的奥西替尼，并将这些数据与早期EGFR TKIs的抑制动力学进行了比较。所述ķ INACT / ķ余数值表示osimertinib使其失活L858R和L858R / T790M与20-和50倍高的总效率，分别相比于WT供。的ķ我和ķ INACT值显示，奥西替尼与L858R的结合力比WT EGFR高3倍，与L858R的反应快3倍，与L858R / T790M相比，与WEGFR的结合更紧密17倍，反应快3倍。我们得出的结论是，奥西替尼通过与Met790相对于Thr790的更强的疏水性相互作用改善了亲和力，克服了T790M突变，并且通过更好地定位丙烯酰胺弹头提高了共价键形成速率，而奥西替尼通过与突变体更好的亲和力和反应性靶向L858R突变。竞争底物ATP的差异结合亲和力的背景。这项工作强调了优化可共价抑制剂的可逆药物-靶标相互作用和失活率以实现靶向突变EGFRs的选择性的重要性。
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