Structure-based identification of potent fibroblast growth factor receptor 4 (FGFR4) inhibitors as potential therapeutics for hepatocellular carcinoma
Lin Fan,
Hui Xie,
Weiyu Wang,
Guizhu Peng,
Zhen Fu,
Qifa Ye
Affiliations
Lin Fan
Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan, Hubei, China
Hui Xie
Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan, Hubei, China
Weiyu Wang
Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan, Hubei, China
Guizhu Peng
Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan, Hubei, China
Zhen Fu
Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan, Hubei, China
Qifa Ye
Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan, Hubei, China
Fibroblast growth factor receptor 4 (FGFR4), a member of the fibroblast growth factor receptor family, plays a crucial role in cell growth, differentiation, and tissue repair. Increased FGFR4 expression has been detected in various cancers, including lung, liver, kidney and pancreatic cancer, making it a potential drug target. In this study, we conducted a structure-based virtual screening campaign to identify potential FGFR4 inhibitors. The retained compounds were further filtered based on pan assay interference compounds (PAINS) and absorption, distribution, metabolism, excretion, and toxicity (ADME/T) properties, leading to the identification of two promising candidates: MFCD00832235 and MFCD00204244. Quantum mechanical (QM) calculations revealed a large Highest Occupied Molecular Orbital (HOMO) and the Lowest Unoccupied Molecular Orbital (LUMO) (HUMO-LUMO) gaps for both compounds, indicating high dynamic stability and low chemical reactivity. Moreover, the stability of MFCD00832235 and MFCD00204244 at the adenosine triphosphate (ATP)-binding site of FGFR4 was confirmed through molecular dynamics (MD) simulations. The molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) approach predicted favorable binding free energy values for both compounds with the target protein. In vitro assay revealed that MFCD00832235 and MFCD00204244 inhibited the growth of HepG2 cells with IC50 values of 47.42 ± 12.93 µM and 77.83 ± 19.17 µM, respectively. Overall, this study suggested that MFCD00832235 and MFCD00204244 were potential FGFR4 inhibitors and may serve as start points for developing novel modulators of FGFR4 for cancer treatment, particularly hepatocellular carcinoma.
