2. Academic Validation
  3. Discovery of CZL-077 as a potent, selective, and orally active p300/CBP bromodomain inhibitor with improved in vivo antitumor efficacy

Discovery of CZL-077 as a potent, selective, and orally active p300/CBP bromodomain inhibitor with improved in vivo antitumor efficacy

  • Eur J Med Chem. 2025 Dec 16:304:118489. doi: 10.1016/j.ejmech.2025.118489.
Zonglong Chen 1,  Ying Zhang 2,  Hui Shen 3,  Hong Yang 4,  Yan Zhang 3,  Qiongyu Shi 4,  Yuxin Yang 1,  Yujie Wang 1,  Ruilin Zhou 5,  Xiaoxue Tan 2,  Haiyan Wan 6,  Yong Xu 7,  Xun Huang 8,  Yingxia Li 9
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, China.
  • 2 School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China; Lingang Laboratory, Shanghai, 200031, China.
  • 3 China-New Zealand Joint Laboratory of Biomedicine and Health, State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Biocomputing, Institute of Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China.
  • 4 Lingang Laboratory, Shanghai, 200031, China.
  • 5 School of Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China.
  • 6 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
  • 7 China-New Zealand Joint Laboratory of Biomedicine and Health, State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Biocomputing, Institute of Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China. Electronic address: [email protected].
  • 8 School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China; Lingang Laboratory, Shanghai, 200031, China; School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China; School of Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China. Electronic address: [email protected].
  • 9 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, China. Electronic address: [email protected].
PMID: 41448045 DOI: 10.1016/j.ejmech.2025.118489
Abstract

Inhibition of E1A binding protein (p300)/CREB binding protein (CBP) bromodomains (BRDs) represents a promising Cancer therapeutic strategy. Herein, we report the discovery of CZL-077, featuring an (R)-2-methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl fragment, as a potent and selective p300/CBP Brd Inhibitor with increased oral exposure and improved in vivo antitumor activity. CZL-077 shows potent inhibitory activity against p300/CBP BRDs and effectively inhibits cell growth with IC50 values of 0.024 μM and 5.6 μM in OPM-2 and 22RV1 cells, respectively. Meanwhile, it exhibits high selectivity over the BRDs of BET proteins and excellent oral exposure, achieving an AUC value of 8823 h∗ng/mL. Compared to CCS1477, it shows comparable in vivo efficacy in the OPM-2 xenograft model and demonstrates more potent antitumor activity in the 22RV1 xenograft model, with tumor growth inhibition values of 56.2% and 72.8%, respectively. Overall, CZL-077 is a promising candidate for the treatment of human Cancer as a p300/CBP Brd Inhibitor.

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