2. Academic Validation
  3. Development of novel N-aryl-2,4-bithiazole-2-amine-based CYP1B1 degraders for reversing drug resistance

Development of novel N-aryl-2,4-bithiazole-2-amine-based CYP1B1 degraders for reversing drug resistance

  • Eur J Med Chem. 2024 Jun 5:272:116488. doi: 10.1016/j.ejmech.2024.116488.
Xiaoxuan Yao 1,  Jianping Mao 1,  Haoyu Zhang 2,  Yi Xiao 1,  Yongjun Wang 3,  Hongzhuo Liu 4
Affiliations

Affiliations

  • 1 Wuya College of Innovation, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, Liaoning, PR China.
  • 2 Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, Liaoning, PR China.
  • 3 Wuya College of Innovation, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, Liaoning, PR China. Electronic address: wangyongjun@syphu.edu.cn.
  • 4 Wuya College of Innovation, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, Liaoning, PR China. Electronic address: liuhongzhuo@syphu.edu.cn.
PMID: 38733885 DOI: 10.1016/j.ejmech.2024.116488
Abstract

Extrahepatic Cytochrome P450 1B1 (CYP1B1), which is highly expressed in non-small cell lung Cancer, is an attractive target for Cancer prevention, therapy, and overcoming drug resistance. Historically, CYP1B1 inhibition has been the primary therapeutic approach for treating CYP1B1-related malignancies, but its success has been limited. This study introduced CYP1B1 degradation as an alternative strategy to counter drug resistance and metastasis in CYP1B1-overexpressing non-small cell lung Cancer A549/Taxol cells via a PROTAC strategy. Our investigation revealed that the identification of the potent CYP1B1 degrader PV2, achieving DC50 values of 1.0 nM and inducing >90 % CYP1B1 degradation at concentrations as low as 10 nM in A549/Taxol cells. Importantly, PV2 enhanced the sensitivity of the A549/Taxol subline to Taxol, possibly due to its stronger inhibitory effects on P-gp through CYP1B1 degradation. Additionally, compared to the CYP1B1 inhibitor A1, PV2 effectively suppressed the migration and invasion of A549/Taxol cells by inhibiting the FAK/Src and EMT pathways. These findings hold promise for a novel therapy targeting advanced CYP1B1+ non-small cell lung Cancer.

Keywords

Antitumor; CYP1B1; Drug resistance; PROTAC.

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