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Structure-Based Drug Design and Synthesis of Novel N-Aryl-2,4-bithiazole-2-amine CYP1B1-Selective Inhibitors in

Jianping Mao1, Dong Wang1, Ping Xu1

  • 1Wuya College of Innovation, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang110016, Liaoning, P. R. China.

Journal of Medicinal Chemistry
|December 13, 2022
PubMed

Insights

This study reveals that CYP1B1 promotes Taxol resistance and cancer spread by activating AKT/ERK1/2 pathways. A novel inhibitor, compound 77, successfully reversed Taxol resistance and inhibited cancer cell migration and invasion.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Cytochrome P450 family 1 subfamily B member 1 (CYP1B1) is a potential cancer therapeutic target.
  • CYP1B1 is overexpressed in Taxol-resistant A549 cells, but its role in drug resistance is not fully understood.

Purpose of the Study:

  • To investigate the role of CYP1B1 in Taxol resistance and cancer migration/invasion.
  • To design and synthesize novel CYP1B1 inhibitors to overcome Taxol resistance.

Main Methods:

  • Bioinformatic analysis to identify pathways correlated with CYP1B1.
  • In vitro experiments using A549 and H460 cells treated with 7,12-dimethylbenz[a]anthracene (DMBA).
  • Design, synthesis, and evaluation of novel N-aryl-2,4-bithiazole-2-amine derivatives as CYP1B1 inhibitors.

Main Results:

  • Bioinformatic analysis linked CYP1B1 to AKT/ERK1/2 and focal adhesion pathways, suggesting its role in Taxol resistance and cancer metastasis.
  • DMBA treatment increased Taxol resistance and promoted migration/invasion in A549 and H460 cells, associated with CYP1B1 upregulation.
  • The synthesized inhibitor, compound 77, selectively inhibited CYP1B1, suppressed AKT/ERK1/2 and FAK/SRC signaling, reversed Taxol resistance, and reduced migration/invasion in A549/Taxol cells.

Conclusions:

  • CYP1B1 plays a significant role in mediating Taxol resistance and facilitating cancer cell migration and invasion.
  • Novel CYP1B1 inhibitors, exemplified by compound 77, hold promise for developing new anticancer strategies against Taxol-resistant cancers.

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