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

  • J Med Chem. 2022 Dec 22;65(24):16451-16480. doi: 10.1021/acs.jmedchem.2c01306.
Jianping Mao  1 ,  Dong Wang  1 ,  Ping Xu  1 ,  Ying Wang  1 ,  Haoyu Zhang  2 ,  Shiyu Wang  1 ,  Feng Xu  1 ,  Jian Wang  2 ,  Fengjiao Zhang  1
Affiliations
  • 1. Wuya College of Innovation, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang110016, Liaoning, P. R. China.
  • 2. Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang110016, Liaoning, P. R. China.
PMID: 36512763 DOI: 10.1021/acs.jmedchem.2c01306
Abstract

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.

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