2. Academic Validation
  3. Discovery and optimization of novel 4-morpholinothieno[3,2-d]pyrimidine derivatives as potent BET inhibitors for cancer therapy

Discovery and optimization of novel 4-morpholinothieno[3,2-d]pyrimidine derivatives as potent BET inhibitors for cancer therapy

  • Bioorg Chem. 2024 Nov 2:153:107929. doi: 10.1016/j.bioorg.2024.107929.
Kai Ran 1,  Yong Li 2,  Yi-Mei Zhang 2,  Dian-Yong Tang 2,  Zhong-Zhu Chen 2,  Zhi-Gang Xu 2,  Li Zhang 3,  Bo-Chu Wang 4,  Jiu-Hong Huang 5
Affiliations

Affiliations

  • 1 College of Pharmacy, National & Local Joint Engineering Research Center of Targeted and Innovative Therapeutics, IATTI, Chongqing University of Arts and Sciences, Chongqing 402160, China; Chongqing Academy of Chinese Materia Medica, No. 34 Nanshan Road, Nan'an District, Chongqing 400065, China; Key Laboratory of Bio-theological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400030, China. Electronic address: kran2021@163.com.
  • 2 College of Pharmacy, National & Local Joint Engineering Research Center of Targeted and Innovative Therapeutics, IATTI, Chongqing University of Arts and Sciences, Chongqing 402160, China.
  • 3 Chongqing Academy of Chinese Materia Medica, No. 34 Nanshan Road, Nan'an District, Chongqing 400065, China.
  • 4 Key Laboratory of Bio-theological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400030, China.
  • 5 College of Pharmacy, National & Local Joint Engineering Research Center of Targeted and Innovative Therapeutics, IATTI, Chongqing University of Arts and Sciences, Chongqing 402160, China. Electronic address: huang_jiuhong@163.com.
PMID: 39509789 DOI: 10.1016/j.bioorg.2024.107929
Abstract

The identification of structurally novel and potently active BET inhibitors represents a significant advancement in the field of Anticancer therapeutics. In the present investigation, leveraging the outcomes of previous screening endeavors, we successfully optimized and synthesized a novel series of bromodomain and extra-terminal (BET) inhibitors with a 4-morpholinothieno[3,2-d]pyrimidine structure. Among the synthesized compounds, compound 6c emerged as a promising candidate, exhibiting exceptional inhibitory activities against various BET isoform proteins, with IC50 values ranging from 3.3 to 42.0 nM. In cellular assays, compound 6c demonstrated robust antiproliferative effects in SU-DHL-4 cells, achieving an IC50 value of 8.6 ± 3.3 nM. Further mechanistic studies revealed that compound 6c effectively decreased the expression of c-Myc, a critical oncogenic driver regulated by the BET protein, and induced cell cycle arrest at the G1 phase, as well as cell Apoptosis, in a dose-dependent manner. Moreover, in-silico prediction of the physiochemical and pharmacokinetic properties clarified that compound 6c has acceptable drug-like profiles. Taken these findings together, compound 6c represents a novel and potent BET inhibitor, thus positioning it as a promising candidate for subsequent pre-clinical evaluations in the realm of Cancer therapy.

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