title: Insight into resistance mechanisms of AZD4547 and E3810 to FGFR1 gatekeeper mutation via theoretical study.
abstract: Inhibitors targeting the amplification of the fibroblast growth factor receptor 1 (FGFR1) have found success in the treatment of FGFR1-positive squamous cell lung and breast cancers. A secondary mutation of gatekeeper residue (V561M) in the binding site has been linked to the acquired resistance. Recently, two well-known small molecule inhibitors of FGFR1, AZD4547 and E3810, reported that the V561M mutation confers significant resistance to E3810, while retaining affinity for AZD4547. FGFR1 is widely investigated as potential therapeutic target, while there are few computational studies made to understand the resistance mechanisms about FGFR1 V561M gatekeeper mutation. In this study, molecular docking, classical molecular dynamics simulations, molecular mechanics/generalized born surface area (MM/GBSA) free energy calculations, and umbrella sampling (US) simulations were carried out to make clear the principle of the binding preference of AZD4547 and E3810 toward FGFR1 V561M gatekeeper mutation. The results provided by MM/GBSA reveal that AZD4547 has similar binding affinity to both FGFR1WTand FGFR1V561M, whereas E3810 has much higher binding affinity to FGFR1WTthan to FGFR1V561M. Comparison of individual energy terms indicates that the major variation of E3810 between FGFR1WTand FGFR1V561Mare van der Waals interactions. In addition, US simulations prove that the potential of mean force (PMF) profile of AZD4547 toward FGFR1WTand FGFR1V561Mhas similar PMF depth. However, the PMF profile of E3810 toward FGFR1WTand FGFR1V561Mhas much higher PMF depth, suggesting that E3810 is more easily dissociated from FGFR1V561Mthan from FGFR1WT. The results not only show the drug-resistance determinants of FGFR1 gatekeeper mutation but also provide valuable implications and provide vital clues for the development of new inhibitors to combat drug resistance.
authors.affiliation: Pharmacy Department, Jining First People's Hospital.
authors.forename: Donglou
authors.initials: D
authors.lastname: Liang
authors.affiliation: Department of Obstetrics, Affiliated Hospital of Jining Medical University, Jining, Shandong.
authors.forename: Qiaowan
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Pharmacy Department, Jining First People's Hospital.
authors.forename: Yujin
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Rheumatology, The First Affiliated Hospital of Wenzhou Medical University.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China.
authors.forename: Wentao
authors.initials: W
authors.lastname: Guo
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology*; D064750:Rabeprazole / Q000737:chemistry / Q000494:pharmacology*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics*
chemical_list: C572463:AZD4547; D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D064750:Rabeprazole; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1
keywords: FGFR1; V561M; gatekeeper mutation; resistance mechanisms; theoretical study