Structure-Based Drug Design and Synthesis of Novel N‑Aryl-2,4-bithiazole-2-amine CYP1B1-Selective Inhibitors in Overcoming Taxol Resistance in A549 Cells

As a promising therapeutic target for cancer, CYP1B1 is overexpressed in Taxol-resistant A549 cells; however, its role in drug resistance still remains unclear. Bioinformatic analysis data indicated that CYP1B1 was closely correlated with AKT/ERK1/2 and focal adhesion pathways, thereby playing an important role in Taxol resistance and cancer migration/invasion. Along similar lines, the AhR agonist 7,12-dimethylbenz­[a]­anthracene (DMBA) enhanced Taxol resistance and promoted migration/invasion of A549 and H460 cells likely stemming from CYP1B1 upregulation. Moreover, 83 novel N-aryl-2,4-bithiazole-2-amine CYP1B1-selective inhibitors were designed and synthesized to verify the role of CYP1B1 in Taxol-resistant A549 cells. Impressively, the most potent and selective one, namely, 77, remarkably inhibited AKT/ERK1/2 and FAK/SRC pathways and thereby reversed Taxol resistance as well as inhibited both migration and invasion of A549/Taxol cells. Collectively, this study not only displayed the role of CYP1B1 in Taxol resistance and cancer migration/invasion but also helped unlock the CYP1B1-oriented anticancer discovery.

细胞色素P450 1B1（CYP1B1）作为极具潜力的癌症治疗靶点，在紫杉醇（Taxol）耐药的A549细胞中呈高表达状态，但其在肿瘤耐药性形成中的具体作用仍未明确。生物信息学分析结果显示，CYP1B1与AKT/ERK1/2及黏着斑通路密切相关，故而在紫杉醇耐药与癌症迁移/侵袭过程中发挥关键作用。与此类似，芳烃受体（AhR）激动剂7,12-二甲基苯并[a]蒽（7,12-dimethylbenz[a]anthracene，DMBA）可增强紫杉醇耐药性，并促进A549与H460细胞的迁移/侵袭能力，其机制可能与CYP1B1表达上调有关。此外，研究人员设计并合成了83种新型N-芳基-2,4-二噻唑-2-胺类CYP1B1选择性抑制剂，以验证CYP1B1在紫杉醇耐药A549细胞中的功能角色。令人瞩目的是，活性与选择性最优的化合物77可显著抑制AKT/ERK1/2及黏着斑激酶（FAK）/Src信号通路，进而逆转紫杉醇耐药性，同时抑制A549/Taxol细胞的迁移与侵袭能力。综上，本研究不仅阐明了CYP1B1在紫杉醇耐药与癌症迁移/侵袭中的关键作用，同时为靶向CYP1B1的抗癌药物研发开辟了全新突破口。