Structure-kinetic relationship reveals the mechanism of selectivity of FAK inhibitors over PYK2

Berger, Benedict‐Tilman; Amaral, Marta; Kokh, Daria B.; Nunes-Alves, Ariane; Müsil, Djordje; Heinrich, Timo; Schröder, Martin; Neil, Rebecca; Wang, Jing; Navrátilová, Iva; Bomke, Joerg; Elkins, J.M.; Müller, Susanne; Frech, Matthias; Wade, Rebecca C.; Knapp, Stefan

doi:10.1016/j.chembiol.2021.01.003

Cited by 48 publications

(60 citation statements)

References 45 publications

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“…It has been shown earlier that protein conformational flexibility plays a crucial role in the residence time 42 . In the context of protein kinases, it was recently discovered that inhibitors that supported a more ordered configuration of the protein were associated with a longer residence time 43 . On the molecular level, explanations such as protein–ligand shape complementary 44 and steric constraints 45 have been suggested to be decisive.…”

Section: Discussionmentioning

confidence: 99%

Decisive role of water and protein dynamics in residence time of p38α MAP kinase inhibitors

et al. 2022

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Target residence time plays a crucial role in the pharmacological activity of small molecule inhibitors. Little is known, however, about the underlying causes of inhibitor residence time at the molecular level, which complicates drug optimization processes. Here, we employ all-atom molecular dynamics simulations (~400 μs in total) to gain insight into the binding modes of two structurally similar p38α MAPK inhibitors (type I and type I½) with short and long residence times that otherwise show nearly identical inhibitory activities in the low nanomolar IC50 range. Our results highlight the importance of protein conformational stability and solvent exposure, buried surface area of the ligand and binding site resolvation energy for residence time. These findings are further confirmed by simulations with a structurally diverse short residence time inhibitor SB203580. In summary, our data provide guidance in compound design when aiming for inhibitors with improved target residence time.

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Section: Discussionmentioning

confidence: 99%

Decisive role of water and protein dynamics in residence time of p38α MAP kinase inhibitors

et al. 2022

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“…Drug selectivity has both thermodynamic and kinetic components enabling compound selection and optimization to be guided by both the affinity for the target as well as the rate constants for formation and breakdown of the drug-target complex. ,,− In our efforts to delineate the factors that underly the implementation of kinetic selectivity, we identified target vulnerability and target turnover as critical factors in modulating the translation of extended target occupancy to prolonged drug activity. , In antibacterial space, time-dependent drug activity can be assessed using the postantibiotic effect (PAE), which is the delay in bacterial growth following compound washout . While several mechanisms can be responsible for the PAE, we previously described correlations between drug-target residence time and PAE demonstrating that the ribosome and the LpxC enzyme from P.…”

Section: Discussionmentioning

confidence: 99%

Impact of Target Turnover on the Translation of Drug-Target Residence Time to Time-Dependent Antibacterial Activity

et al. 2021

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The translation of time-dependent drug-target occupancy to extended pharmacological activity at low drug concentration depends on factors such as target vulnerability and the rate of target turnover. Previously, we demonstrated that the postantibiotic effect (PAE) caused by inhibitors of bacterial drug targets could be used to assess target vulnerability, and that high levels of target vulnerability coupled with relatively low rates of target resynthesis resulted in a strong correlation between drug-target residence time and the PAE following compound washout. Although the residence time of inhibitors on UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC) in Pseudomonas aeruginosa (paLpxC) results in significant PAE, inhibitors of the equivalent enzyme in Escherichia coli (ecLpxC) do not cause a PAE. Hyperactivity of the fatty acid biosynthesis enzyme FabZ or the inclusion of sub-MIC levels of azithromycin lead to the observation of a PAE for three inhibitors of ecLpxC. FabZ hyperactivity has been shown to stabilize ecLpxC, and using mass spectrometry, we demonstrate that the appearance of a PAE can be directly linked to a 3-fold increase in the stability of ecLpxC. These studies substantiate the importance of target turnover in time-dependent drug activity.

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“…The central kinase domain has an activation loop that contains two important Tyr sites at576 and 577 which can be phosphorylated by Src and stimulate FAK kinase activity in turn [ 14 ]. The classic mechanism of FAK activation involves integrin receptor clustering upon the binding of cells to extracellular matrix (ECM) proteins, which leads to FAK autophosphorylation at Tyr397.…”

Section: Fak Structural Features and The Function In Cancermentioning

confidence: 99%

“…Tyr861 and Tyr925 can be phosphorylated to form binding sites for proteins containing the SH2 structural domain. Thus, the C-terminus structural domain is also involved in regulating endogenous FAK function [ 14 , 15 ].…”

Section: Fak Structural Features and The Function In Cancermentioning

confidence: 99%

Focal adhesion kinase inhibitors, a heavy punch to cancer

et al. 2021

Discov Onc

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Kinases are the ideal druggable targets for diseases and especially were highlighted on cancer therapy. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase and its aberrant signaling extensively implicates in the progression of most cancer types, involving in cancer cell growth, adhesion, migration, and tumor microenvironment (TME) remodeling. FAK is commonly overexpressed and activated in a variety of cancers and plays as a targetable kinase in cancer therapy. FAK inhibitors already exhibited promising performance in preclinical and early-stage clinical trials. Moreover, substantial evidence has implied that targeting FAK is more effective in combination strategy, thereby reversing the failure of chemotherapies or targeted therapies in solid tumors. In the current review, we summarized the drug development progress, chemotherapy strategy, and perspective view for FAK inhibitors.

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Structure-kinetic relationship reveals the mechanism of selectivity of FAK inhibitors over PYK2

Cited by 48 publications

References 45 publications

Decisive role of water and protein dynamics in residence time of p38α MAP kinase inhibitors

Decisive role of water and protein dynamics in residence time of p38α MAP kinase inhibitors

Impact of Target Turnover on the Translation of Drug-Target Residence Time to Time-Dependent Antibacterial Activity

Focal adhesion kinase inhibitors, a heavy punch to cancer

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