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首页> 外文期刊>RSC Advances >Computer-aided drug design, synthesis and identification of disulfide compounds as novel and potential allosteric PAK1 inhibitors
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Computer-aided drug design, synthesis and identification of disulfide compounds as novel and potential allosteric PAK1 inhibitors

机译：计算机辅助药物设计，合成及二硫化物化合物的鉴定为新颖的和潜在的颠振PAK1抑制剂

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摘要

p21-activated kinase 1 (PAK1) is an evolutionarily conserved serine/threonine protein kinase, which has been considered as one of the key regulatory factors in signaling network of tumor cells. Therefore, inhibition of PAK1 may be a potential approach to treat many types of solid tumors. Several allosteric inhibitors of PAK1 have been identified, and the most well known one is IPA-3. But its biological activity is not satisfied, and the structure activity relationship (SAR) of PAK1 allosteric inhibitors is unclear. In this study, we designed and synthesized 13 potential allosteric inhibitors by using computer-aided drug design based on the structure of the existing PAK1 allosteric inhibitors. All the compounds were characterized by H-1-NMR and C-13-NMR, among which six were not reported previously. SAR was investigated by pharmacological studies and In03 and In06 showed increased PAK1 inhibition than previously reported IPA-3. These findings could guide further structure optimization of PAK1 inhibitors.
机译：P21活化激酶1（PAK1）是一种进化保守的丝氨酸/苏氨酸蛋白激酶，被认为是肿瘤细胞信号网络中的关键调节因子之一。因此，对PAK1的抑制可以是治疗许多类型的实体瘤的潜在方法。已经鉴定了几种PAK1的变构抑制剂，最着名的是IPA-3。但其生物学活性不满足，PAK1变构抑制剂的结构活动关系（SAR）尚不清楚。在这项研究中，我们通过基于现有PAK1变构抑制剂的结构使用计算机辅助药物设计设计和合成了13个潜在的颠覆抑制剂。所有化合物的特征在于H-1-NMR和C-13-NMR，其中六个未以前报道六个。通过药理学研究和INO 9和IN06研究了SAR显示比以前报道的IPA-3增加了PAK1抑制。这些发现可以指导PAK1抑制剂的进一步结构优化。

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  • 来源
    《RSC Advances》 |2018年第22期|共8页
  • 作者

    Huang Hanwei; Jiang Hailun; Zhang Xiangyu; Li Wei; Wang Pengliang; Liu Funan; Wang Jian; Bai Mingfeng; Cheng Maosheng;

  • 作者单位

    China Med Univ Affiliated Hosp 1 Dept Surg Oncol &

    Gen Surg 155 Nanjing North St Shenyang 110001 Liaoning Peoples R China;

    Shenyang Pharmaceut Univ Minist Educ Key Lab Struct Based Drug Design &

    Discovery Shenyang Liaoning Peoples R China;

    Shenyang Pharmaceut Univ Minist Educ Key Lab Struct Based Drug Design &

    Discovery Shenyang Liaoning Peoples R China;

    Shenyang Univ Chem Technol Dept Pharmaceut Engn Shenyang Liaoning Peoples R China;

    China Med Univ Affiliated Hosp 1 Dept Surg Oncol &

    Gen Surg 155 Nanjing North St Shenyang 110001 Liaoning Peoples R China;

    China Med Univ Affiliated Hosp 1 Dept Surg Oncol &

    Gen Surg 155 Nanjing North St Shenyang 110001 Liaoning Peoples R China;

    Shenyang Pharmaceut Univ Minist Educ Key Lab Struct Based Drug Design &

    Discovery Shenyang Liaoning Peoples R China;

    Vanderbilt Univ Med Ctr VUIIS Nashville TN 37232 USA;

    Shenyang Pharmaceut Univ Minist Educ Key Lab Struct Based Drug Design &

    Discovery Shenyang Liaoning Peoples R China;

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  • 正文语种 eng
  • 中图分类 化学;
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