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

Wan-Hsi Shih; Han-Li Huang; Wei-Chun HuangFu; Tony Eight Lin; Tzu-Ying Sung; Mu-Chun Li; Guan-Lin Huang; Yu-Wei Chang; Shih-Chung Yen; Hsing-Pang Hsieh; Kai-Cheng Hsu; Shiow-Lin Pan

doi:10.1016/j.ijbiomac.2024.137296

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. Epub 2024 Nov 6.

Authors

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: [email protected].
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: [email protected].

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.

MeSH terms

Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Apoptosis* / drug effects
Carcinoma, Pancreatic Ductal* / drug therapy
Carcinoma, Pancreatic Ductal* / metabolism
Carcinoma, Pancreatic Ductal* / pathology
Cell Line, Tumor
Cell Proliferation* / drug effects
Cell Survival / drug effects
Drug Discovery
Humans
Molecular Docking Simulation
Pancreatic Neoplasms* / drug therapy
Pancreatic Neoplasms* / metabolism
Pancreatic Neoplasms* / pathology
Phosphorylation / drug effects
Protein Kinase Inhibitors* / chemistry
Protein Kinase Inhibitors* / pharmacology
Protein Serine-Threonine Kinases* / antagonists & inhibitors
Protein Serine-Threonine Kinases* / metabolism
Proto-Oncogene Proteins c-akt / antagonists & inhibitors
Proto-Oncogene Proteins c-akt / metabolism
Signal Transduction / drug effects

Substances

Protein Serine-Threonine Kinases
TBK1 protein, human
Protein Kinase Inhibitors
Antineoplastic Agents
Proto-Oncogene Proteins c-akt