2. Academic Validation
  3. Design and synthesis of guanidino derivatives of benzoate esters as SIRT6 inhibitors

Design and synthesis of guanidino derivatives of benzoate esters as SIRT6 inhibitors

  • Bioorg Med Chem Lett. 2025 Oct 7:130:130430. doi: 10.1016/j.bmcl.2025.130430.
Yongzhi Ma 1,  Minni Ding 1,  Kewang Yu 1,  Siyu Wang 1,  Siyuan Wang 2,  Hao Cao 3,  Huiming Hua 4,  Dahong Li 5
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China.
  • 2 College of Pharmacy, Shenzhen Technology University, Shenzhen 518118, PR China.
  • 3 School of Life Science and Biopharmaceutics, and Key Laboratory of Microbial Pharmaceutics, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, Liaoning Province, PR China. Electronic address: [email protected].
  • 4 Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China. Electronic address: [email protected].
  • 5 Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China. Electronic address: [email protected].
PMID: 41061899 DOI: 10.1016/j.bmcl.2025.130430
Abstract

SIRT6 is a key member of the Sirtuin family and plays a crucial role in regulating cellular metabolism, maintaining genomic stability, and influencing the aging process. SIRT6 inhibitors have garnered significant attention due to their potential therapeutic value in treating Cancer, inflammation, and metabolic diseases. In this study, a high-throughput virtual screening approach, combined with FLUOR DE LYS detection, was employed to identify the guanidino benzoate ester compound Hit 13, which exhibits SIRT6 inhibitory activity. Subsequent structural optimization yielded a series of analogs. Among these, compounds 15, 25, and 27 demonstrated SIRT6 inhibitory activity and selectivity. Combination therapy, an emerging strategy in Cancer treatment, has demonstrated promising efficacy. The combination of SIRT6 inhibitors with chemotherapy drugs can produce synergistic cytotoxic effects, reverse drug resistance, and has the potential to reduce chemotherapy doses while mitigating side effects. When compound 15 or 25 was combined with chemotherapy agents, they significantly enhanced the anti-proliferative effects of these drugs on tumor cells. This sensitization effect was particularly pronounced with doxorubicin, which reduced its IC50 value against MCF-7 cells from 11 μM to 4 μM. Compounds 15 and 25 may serve as promising lead compounds for drug development targeting SIRT6.

Keywords

Anti-tumor; Combination therapy; Inhibitor; SIRT6.

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