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Structural optimization of diphenylpyrimidine scaffold as potent and selective epidermal growth factor receptor inhibitors against L858R/T790M resistance mutation in nonsmall cell lung cancer
Chemical Biology & Drug Design ( IF 3.2 ) Pub Date : 2018-08-26 , DOI: 10.1111/cbdd.13370 Yuanyuan Yi 1 , Luhong Wang 2 , Dan Zhao 2 , Shanshan Huang 2 , Changyuan Wang 2 , Zhihao Liu 2, 3 , Huijun Sun 2 , Kexin Liu 2 , Xiaodong Ma 2 , Yanxia Li 1
Chemical Biology & Drug Design ( IF 3.2 ) Pub Date : 2018-08-26 , DOI: 10.1111/cbdd.13370 Yuanyuan Yi 1 , Luhong Wang 2 , Dan Zhao 2 , Shanshan Huang 2 , Changyuan Wang 2 , Zhihao Liu 2, 3 , Huijun Sun 2 , Kexin Liu 2 , Xiaodong Ma 2 , Yanxia Li 1
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A new class of thiodiphenylpyrimidine analogs (Thio‐DPPY) were synthesized as potent and selective EGFR T790M inhibitors to overcome gefitinib resistance in nonsmall cell lung cancer (NSCLC). This structural optimization led to the identification of two potent EGFRT790M/L858R inhibitors, 14a and 14e, which possess IC50 values of 27.5 and 9.1 nM, respectively. Moreover, compounds 14a (SI > 36.4) and 14e (SI > 109.9) exhibited high selectivity and low activity against the wild‐type EGFR (IC50 > 1,000 nM). In particular, compound 14a also displayed strong potency against EGFRT790M‐mutated H1975 cells (IC50 = 0.074 μM), but weak activity toward normal cells HBE (IC50 > 40 μM) and LO‐2 (IC50 = 9.891 μM). It is important that compound 14a (SI = 52.6) significantly improved the selectivity against mutant H1975 cells over wild‐type A431 cells than rociletinib (SI = 6.0), thus revealing its slight cell cytotoxicity. This study provides a promising Thio‐DPPY derivative as enhanced EGFR T790M inhibitor, and also revealed valuable clues for further optimization of DPPY scaffold to overcome NSCLC resistance.
中文翻译：
结构优化的二苯基嘧啶支架作为有效和选择性的表皮生长因子受体抑制剂在非小细胞肺癌中抵抗L858R / T790M耐药性突变的机制
合成了一类新型的硫代二苯基嘧啶类似物（Thio-DPPY）作为有效和选择性的EGFR T790M抑制剂，以克服非小细胞肺癌（NSCLC）中的吉非替尼耐药性。这种结构优化导致鉴定了两种有效的EGFR T 790M / L858R抑制剂1 4a和14e，其IC 50值分别为27.5和9.1 nM。此外，化合物14a（SI> 36.4）和14e（SI> 109.9）对野生型EGFR表现出高选择性和低活性（IC 50 > 1,000 nM）。特别地，化合物14a还显示出针对EGFR T 790M的强力突变的H1975细胞（IC 50 = 0.074μM ），但对正常细胞HBE（IC 50 > 40μM）和LO-2（IC 50 = 9.891μM）的活性较弱。重要的是，化合物14a（SI = 52.6）比rociletinib（SI = 6.0）显着提高了对野生型A431细胞的突变H1975细胞的选择性，从而显示出轻微的细胞毒性。这项研究提供了有希望的Thio-DPPY衍生物作为增强的EGFR T790M抑制剂，并且还揭示了进一步优化DPPY支架以克服NSCLC耐药性的宝贵线索。
更新日期：2018-08-26
中文翻译：
结构优化的二苯基嘧啶支架作为有效和选择性的表皮生长因子受体抑制剂在非小细胞肺癌中抵抗L858R / T790M耐药性突变的机制
合成了一类新型的硫代二苯基嘧啶类似物（Thio-DPPY）作为有效和选择性的EGFR T790M抑制剂，以克服非小细胞肺癌（NSCLC）中的吉非替尼耐药性。这种结构优化导致鉴定了两种有效的EGFR T 790M / L858R抑制剂1 4a和14e，其IC 50值分别为27.5和9.1 nM。此外，化合物14a（SI> 36.4）和14e（SI> 109.9）对野生型EGFR表现出高选择性和低活性（IC 50 > 1,000 nM）。特别地，化合物14a还显示出针对EGFR T 790M的强力突变的H1975细胞（IC 50 = 0.074μM ），但对正常细胞HBE（IC 50 > 40μM）和LO-2（IC 50 = 9.891μM）的活性较弱。重要的是，化合物14a（SI = 52.6）比rociletinib（SI = 6.0）显着提高了对野生型A431细胞的突变H1975细胞的选择性，从而显示出轻微的细胞毒性。这项研究提供了有希望的Thio-DPPY衍生物作为增强的EGFR T790M抑制剂，并且还揭示了进一步优化DPPY支架以克服NSCLC耐药性的宝贵线索。
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