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  3. Discovery of berberine analogs as potent and highly selective p300/CBP HAT inhibitors

Discovery of berberine analogs as potent and highly selective p300/CBP HAT inhibitors

  • Bioorg Chem. 2023 Sep:138:106597. doi: 10.1016/j.bioorg.2023.106597.
Xue Zhong 1,  Huiwen Deng 1,  Min Long 1,  Honglu Yin 1,  Qiu Zhong 2,  Shilong Zheng 2,  Tao Gong 1,  Ling He 3,  Guangdi Wang 4,  Qiu Sun 5
Affiliations

Affiliations

  • 1 Key Laboratory of Drug-Targeting and Drug-Delivery Systems of the Ministry of Education, Department of Medicinal Chemistry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, Department of Medicinal Chemistry, West China School of Pharmacy, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 2 Department of Chemistry and RCMI Cancer Research Center, Xavier University of Louisiana, New Orleans, LA 70125, USA.
  • 3 Key Laboratory of Drug-Targeting and Drug-Delivery Systems of the Ministry of Education, Department of Medicinal Chemistry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, Department of Medicinal Chemistry, West China School of Pharmacy, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: heling2012@scu.edu.cn.
  • 4 Department of Chemistry and RCMI Cancer Research Center, Xavier University of Louisiana, New Orleans, LA 70125, USA. Electronic address: gwang@xula.edu.
  • 5 Key Laboratory of Drug-Targeting and Drug-Delivery Systems of the Ministry of Education, Department of Medicinal Chemistry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, Department of Medicinal Chemistry, West China School of Pharmacy, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China; West China Medical Publishers, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: sunqiu@scu.edu.cn.
PMID: 37245245 DOI: 10.1016/j.bioorg.2023.106597
Abstract

The protein p300 is a positive regulator of Cancer progression and is related to many human pathological conditions. To find effective p300/CBP HAT inhibitors, we screened an internal compound library and identified berberine as a lead compound. Next, we designed, synthesized, and screened a series of novel berberine analogs, and discovered that analog 5d was a potent and highly selective p300/CBP HAT inhibitor with IC50 values of 0.070 μM and 1.755 μM for p300 and CBP, respectively. Western blotting further proved that 5d specifically decreased H3K18Ac and interfere with the function of Histone Acetyltransferase. Although 5d had only a moderate inhibitory effect on the MDA-MB-231 cell line, 5d suppressed the growth of 4T1 tumor growth in mice with a tumor weight inhibition ratio (TWI) of 39.7%. Further, liposomes-encapsulated 5d increased its inhibition of tumor growth to 57.8 % TWI. In addition, 5d has no obvious toxicity to the main organ of mice and the pharmacokinetic study confirmed that 5d has good absorption properties in vivo.

Keywords

Berberine analogs; Histone acetyltransferase; p300/CBP HAT inhibitors.

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