State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization and Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, China.
School of Biological and Medical Engineering, Hefei University of Technology, Hefei, 230009, China.
Eur J Med Chem. 2021 Feb 5;211:113022. doi: 10.1016/j.ejmech.2020.113022. Epub 2020 Nov 13.
Multitarget drugs have emerged as a promising treatment modality in modern anticancer therapy. Taking advantage of the synergy of NAMPT and EGFR inhibition, we have developed the first compounds that serve as dual inhibitors of NAMPT and EGFR. On the basis of CHS828 and erlotinib, a series of hybrid molecules were successfully designed and synthesized by merging of the pharmacophores. Among the compounds that were synthesized, compound 28 showed good NAMPT and EGFR inhibition, and excellent in vitro anti-proliferative activity. Compound 28, which is a new chemotype devoid of a Michael receptor, strongly inhibited the proliferation of several cancer cell lines, including H1975 non-small cell lung cancer cells harboring the EGFR mutation. More importantly, it imparted significant in vivo antitumor efficacy in a human NSCLC (H1975) xenograft nude mouse model. This study provides promising leads for the development of novel antitumor agents and valuable pharmacological probes for the assessment of dual inhibition in NAMPT and EGFR pathway with a single inhibitor.
多靶点药物已成为现代抗癌治疗中一种有前途的治疗方式。利用 NAMPT 和 EGFR 抑制的协同作用，我们开发了首个作为 NAMPT 和 EGFR 双重抑制剂的化合物。在 CHS828 和厄洛替尼的基础上，通过融合药效团成功设计并合成了一系列杂合分子。在合成的化合物中，化合物 28 表现出良好的 NAMPT 和 EGFR 抑制作用，以及优异的体外抗增殖活性。化合物 28 是一种新型的无迈克尔受体的化学型，强烈抑制了包括携带 EGFR 突变的非小细胞肺癌细胞 H1975 在内的几种癌细胞系的增殖。更重要的是，它在人非小细胞肺癌（H1975）异种移植裸鼠模型中表现出显著的体内抗肿瘤疗效。这项研究为开发新型抗肿瘤药物提供了有前途的先导化合物，并为评估 NAMPT 和 EGFR 通路的双重抑制提供了有价值的药理学探针，而只需使用一种抑制剂。
