2. Academic Validation
  3. Discovery of novel TANK-Binding Kinase 1 (TBK1) inhibitor against pancreatic ductal adenocarcinoma

Discovery of novel TANK-Binding Kinase 1 (TBK1) inhibitor against pancreatic ductal adenocarcinoma

  • Int J Biol Macromol. 2024 Dec;283(Pt 1):137296. doi: 10.1016/j.ijbiomac.2024.137296.
Wan-Hsi Shih 1,  Han-Li Huang 2,  Wei-Chun HuangFu 3,  Tony Eight Lin 1,  Tzu-Ying Sung 4,  Mu-Chun Li 5,  Guan-Lin Huang 6,  Yu-Wei Chang 7,  Shih-Chung Yen 8,  Hsing-Pang Hsieh 9,  Kai-Cheng Hsu 10,  Shiow-Lin Pan 11
Affiliations

Affiliations

  • 1 Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
  • 2 TMU Research Center for Drug Discovery, Taipei Medical University, Taipei, Taiwan; TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan.
  • 3 Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan.
  • 4 Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
  • 5 Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County, Taiwan; Biomedical Translation Research Center, Academia Sinica, Taipei, Taiwan.
  • 6 Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County, Taiwan.
  • 7 Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Keelung Medical Center, Keelung, Taiwan.
  • 8 Warshel Institute for Computational Biology, The Chinese University of Hong Kong, Shenzhen, Guangdong, People's Republic of China.
  • 9 Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County, Taiwan; Biomedical Translation Research Center, Academia Sinica, Taipei, Taiwan; Department of Chemistry, National Tsing Hua University, Hsinchu, Taiwan.
  • 10 Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; TMU Research Center for Drug Discovery, Taipei Medical University, Taipei, Taiwan; TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan; Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. Electronic address: piki@tmu.edu.tw.
  • 11 Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; TMU Research Center for Drug Discovery, Taipei Medical University, Taipei, Taiwan; TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan. Electronic address: slpan@tmu.edu.tw.
PMID: 39515714 DOI: 10.1016/j.ijbiomac.2024.137296
Abstract

Pancreatic ductal adenocarcinoma (PDAC) has limited treatment options, underscoring the urgent need for developing new therapies. The upregulation of TBK1 activity plays a crucial role in multiple pancreatic cancer-related signaling pathways, suggesting that inhibiting the kinase activity of TBK1 could be a promising strategy. Herein, we discovered a novel TBK1 Inhibitor, LIB3S0280, using a structure-based virtual screening (SBVS) strategy. In the anti-proliferative and viability assays, LIB3S0280 showed significant inhibition against pancreatic Cancer cell lines that highly express TBK1 with the GI50 values of 2.24 and 4.71 μM and IC50 values of 6.64 and 10.98 μM at 96 h. For the downstream targets, LIB3S0280 can inhibit TBK1 downstream signaling by decreasing the phosphorylation of IκBα and Akt better than a known TBK1 Inhibitor, BX-795. Furthermore, PDAC cells were arrested in G2/M and underwent Apoptosis or senescence with the treatment of LIB3S0280. These findings suggest that TBK1 Inhibitor LIB3S0280 has great potential as a lead compound in the further development of a novel treatment for PDAC.

Keywords

Apoptosis; Pancreatic ductal adenocarcinoma; Senescence; Structure-based virtual screening; TANK-binding kinase 1.

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