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  3. A novel SIK2 inhibitor SIC-19 exhibits synthetic lethality with PARP inhibitors in ovarian cancer

A novel SIK2 inhibitor SIC-19 exhibits synthetic lethality with PARP inhibitors in ovarian cancer

  • Drug Resist Updat. 2024 May:74:101077. doi: 10.1016/j.drup.2024.101077.
Fang Wang 1,  Xuejiao Yu 2,  Jun Qian 1,  Yumin Cao 1,  Shunli Dong 3,  Shenghua Zhan 4,  Zhen Lu 5,  Robert C Bast Jr 5,  Qingxia Song 6,  Youguo Chen 7,  Yi Zhang 8,  Jinhua Zhou 9
Affiliations

Affiliations

  • 1 Department of Obstetrics and Gynecology, The First Affiliated Hospital of Soochow University, Suzhou, China.
  • 2 Department of Imaging Department, The First Affiliated Hospital of Soochow University, Suzhou, China.
  • 3 Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
  • 4 Department of Pathology, The First Affiliated Hospital of Soochow University, Suzhou, China.
  • 5 Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
  • 6 Department of Obstetrics and Gynecology, Nanjing University of Chinese Medicine Affiliated Suzhou Hospital, Suzhou, China.
  • 7 Department of Obstetrics and Gynecology, The First Affiliated Hospital of Soochow University, Suzhou, China. Electronic address: chenyouguo@suda.edu.cn.
  • 8 Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China. Electronic address: zhangyi@suda.edu.cn.
  • 9 Department of Obstetrics and Gynecology, The First Affiliated Hospital of Soochow University, Suzhou, China. Electronic address: jsjhzh@126.com.
PMID: 38518726 DOI: 10.1016/j.drup.2024.101077
Abstract

Purpose: Ovarian Cancer patients with HR proficiency (HRP) have had limited benefits from PARP Inhibitor treatment, highlighting the need for improved therapeutic strategies. In this study, we developed a novel SIK2 Inhibitor, SIC-19, and investigated its potential to enhance the sensitivity and expand the clinical utility of PARP inhibitors in ovarian Cancer.

Methods: The SIK2 protein was modeled using a Molecular Operating Environment (MOE), and the most favorable model was selected based on a GBVI/WSA dG scoring function. The Chembridge Compound Library was screened, and the top 20 candidate compounds were tested for their interaction with SIK2 and downstream substrates, AKT-pS473 and MYLK-pS343. SIC-19 emerged as the most promising drug candidate and was further evaluated using multiple assays.

Results: SIC-19 exhibited selective and potent inhibition of SIK2, leading to its degradation through the ubiquitination pathway. The IC50 of SIC-19 correlated inversely with endogenous SIK2 expression in ovarian Cancer cell lines. Treatment with SIC-19 significantly inhibited Cancer cell growth and sensitized cells to PARP inhibitors in vitro, as well as in ovarian Cancer organoids and xenograft models. Mechanistically, SIK2 knockdown and SIC-19 treatment reduced RAD50 phosphorylation at Ser635, prevented nuclear translocation of RAD50, disrupted nuclear filament assembly, and impaired DNA homologous recombination repair, ultimately inducing Apoptosis. These findings highlight the crucial role of SIK2 in the DNA HR repair pathway and demonstrate the significant PARP Inhibitor sensitization achieved by SIC-19 in ovarian Cancer.

Conclusions: SIC-19, a novel SIK2 Inhibitor, effectively inhibits tumor cell growth in ovarian Cancer by interfering with RAD50-mediated DNA HR repair. Furthermore, SIC-19 enhances the efficacy of PARP inhibitors, providing a promising therapeutic strategy to improve outcomes for ovarian Cancer patients.

Keywords

Ovarian cancer; PARP inhibitor; RAD50; SIC-19; SIK2.

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