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^L858R/T790M 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.

在现代抗癌治疗中，多靶点药物已成为一种有前途的治疗方式。利用NAMPT和EGFR抑制的协同作用，我们开发了首个可用作NAMPT和EGFR双重抑制剂的化合物。在CHS828和厄洛替尼的基础上，通过药效基团的合并，成功设计并合成了一系列杂交分子。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，并具有出色的体外抗增殖活性。化合物28是不含Michael受体的新型化学型，可强烈抑制几种癌细胞系的增殖，包括具有EGFR ^{L858R / T790M的}H1975非小细胞肺癌细胞突变。更重要的是，它在人NSCLC（H1975）异种移植裸鼠模型中具有显着的体内抗肿瘤功效。这项研究为开发新型抗肿瘤药物和有价值的药理探针提供了有希望的线索，这些药物可用于评估单一抑制剂对NAMPT和EGFR途径的双重抑制作用。