Structure-Based Design, Synthesis, and Characterization of the First Irreversible Inhibitor of Focal Adhesion Kinase

Yen‐Pon, Expédite; Li, Bo; Acebrón-García-de-Eulate, Marta; Tomkiewicz-Raulet, Céline; Dawson, John C.; Lietha, Daniel; Frame, Margaret C.; Coumoul, Xavier; Garbay, Christiane; Ethève-Quelquejeu, Mélanie; Chen, Huixiong

doi:10.1021/acschembio.8b00250

Cited by 29 publications

(27 citation statements)

References 31 publications

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“…In accordance with Chen's findings (Yen-Pon et al, 2018), we also discovered small, fully-synthetic covalent binders of FAK C427 via a cysteine-reactive covalent ligand screen using gel-based ABPP against the pure human FAK1 kinase domain ( Fig. S2-S4; Table S2).…”

Section: Main Textsupporting

confidence: 86%

“…2H). While this manuscript was under revision, an elegant study describing the first structure-guided design, synthesis, and characterization of a FAK1 inhibitor that also covalently targeted C427 of FAK1 and inhibited its function was reported (Yen-Pon et al, 2018). Importantly, this report gives further credence to our hypothesis of the functional relevance of this cysteine and its effects on cancer cell proliferation.…”

Section: Main Textmentioning

confidence: 76%

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Parthenolide Covalently Targets and Inhibits Focal Adhesion Kinase in Breast Cancer Cells

Berdan¹,

Ho²,

Lehtola³

et al. 2019

Preprint

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Parthenolide, a natural product from the feverfew plant and member of the large family of sesquiterpene lactones, exerts multiple biological and therapeutic activities including anti-inflammatory and anti-cancer effects. Herein, we further study parthenolide mechanism of action using activity-based protein profiling (ABPP)-based chemoproteomic platforms to map additional covalent targets engaged by parthenolide in human breast cancer cells. We find that parthenolide, as well as other related exocyclic methylene lactonecontaining sesquiterpenes, covalently modify cysteine 427 (C427) of focal adhesion kinase 1 (FAK1) leading to impairment of FAK1-dependent signaling pathways and breast cancer cell proliferation, survival, and motility.These studies reveal a novel functional target exploited by members of a large family of anticancer natural products.

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Section: Main Textsupporting

confidence: 86%

Section: Main Textmentioning

confidence: 76%

Parthenolide Covalently Targets and Inhibits Focal Adhesion Kinase in Breast Cancer Cells

Berdan¹,

Ho²,

Lehtola³

et al. 2019

Preprint

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“…Cys502 in the active site of FAK is known as a key residue for binding with ligands [ 26 ]. This interaction can be found in many X-ray crystallography structures with various inhibitors [ 24 , 27 , 28 , 29 , 30 ]. Moreover, it has been found that three bromine atoms of 14B can form halogen bonds: bromine at C4 with the carbonyl group of Ser568 (3.3 Å) and with the more distant carbonyl group of Asn551 (3.6 Å), bromine at C6 with the carbonyl group of Ile428 (3.6 Å), and bromine at C7 with the carbonyl group of Glu506 (3.7 Å).…”

Section: Resultsmentioning

confidence: 95%

Synergistic Interactions of 5-Fluorouracil with Inhibitors of Protein Kinase CK2 Correlate with p38 MAPK Activation and FAK Inhibition in the Triple-Negative Breast Cancer Cell Line

Wińska

Karatsai

Staniszewska

et al. 2020

IJMS

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Background: The combination effect of 5-fluorouracil (5-FU) with either CX-4945 or a new inhibitor of protein kinase CK2, namely 14B (4,5,6,7-tetrabromo-1-(3-bromopropyl)-2-methyl-1H-benzimidazole), on the viability of MCF-7 and triple-negative MDA-MB-231 breast cancer cell lines was studied. Methods: Combination index (CI) values were determined using an MTT-based assay and the Chou-Talalay model. The effect of the tested drug combinations on pro-apoptotic properties and cell cycle progression was examined using flow cytometry. The activation of FAK, p38 MAPK, and ERK1/2 kinases and the expression of selected pro-apoptotic markers in MDA-MB-231 cell line after the combined treatment were evaluated by the western blot method. Confocal microscopy was used to examine actin network in MDA-MB-231. Results: Our results showed that a synergistic effect (CI < 1) occurred in MDA-MB-231 after treatment with both combinations of 5-FU with 14B or CX-4945, whereas the combination of 5-FU and 14B evoked an antagonistic effect in MCF-7. We conclude that the synergistic interactions (CI < 1) observed for both the combinations of 5-FU and 14B or CX-4945 in MDA-MB-231 correlated with an activation of p38 MAPK, inhibition of FAK, increased expression of apoptogenic markers, prolongation of S-phase of cell cycle, and destabilization of actin network. Conclusions: The obtained results support the recent observation that CK2 inhibitors can improve 5-FU-based anticancer therapy and FAK kinase can be an attractive molecular target in breast cancer therapy.

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“…Therefore, this cysteine residue could be used as the nucleophilic group for the design of covalent FAK inhibitors. Chen’s group successfully discovered novel FAK inhibitors by the introduction of an acrylamide moiety to the pyrimidine scaffold of TAE-226 in 2018 ( Figure 13 ) [ 90 ]. These compounds with appropriate linkers could ensure that acrylamide group can be in proximity to Cys427 of FAK protein and the 2,4-diphenylamine pyrimidine as a core scaffold to maintain the binding affinity with the FAK protein.…”

Section: The Discovery Of Fak Inhibitors and Their Therapeutic Significancementioning

confidence: 99%

“…Therefore, this cysteine residue could be used as the nucleophilic group for the design of covalent FAK inhibitors. Chen's group successfully discovered novel FAK inhibitors by the introduction of an acrylamide moiety to the pyrimidine scaffold of TAE-226 in 2018 (Figure13)[90]. These compounds with appropriate linkers could ensure that…”

mentioning

confidence: 99%

Drug Discovery Targeting Focal Adhesion Kinase (FAK) as a Promising Cancer Therapy

Pang

Liu

et al. 2021

Molecules

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FAK is a nonreceptor intracellular tyrosine kinase which plays an important biological function. Many studies have found that FAK is overexpressed in many human cancer cell lines, which promotes tumor cell growth by controlling cell adhesion, migration, proliferation, and survival. Therefore, targeting FAK is considered to be a promising cancer therapy with small molecules. Many FAK inhibitors have been reported as anticancer agents with various mechanisms. Currently, six FAK inhibitors, including GSK-2256098 (Phase I), VS-6063 (Phase II), CEP-37440 (Phase I), VS-6062 (Phase I), VS-4718 (Phase I), and BI-853520 (Phase I) are undergoing clinical trials in different phases. Up to now, there have been many novel FAK inhibitors with anticancer activity reported by different research groups. In addition, FAK degraders have been successfully developed through “proteolysis targeting chimera” (PROTAC) technology, opening up a new way for FAK-targeted therapy. In this paper, the structure and biological function of FAK are reviewed, and we summarize the design, chemical types, and activity of FAK inhibitors according to the development of FAK drugs, which provided the reference for the discovery of new anticancer agents.

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Structure-Based Design, Synthesis, and Characterization of the First Irreversible Inhibitor of Focal Adhesion Kinase

Cited by 29 publications

References 31 publications

Parthenolide Covalently Targets and Inhibits Focal Adhesion Kinase in Breast Cancer Cells

Parthenolide Covalently Targets and Inhibits Focal Adhesion Kinase in Breast Cancer Cells

Synergistic Interactions of 5-Fluorouracil with Inhibitors of Protein Kinase CK2 Correlate with p38 MAPK Activation and FAK Inhibition in the Triple-Negative Breast Cancer Cell Line

Drug Discovery Targeting Focal Adhesion Kinase (FAK) as a Promising Cancer Therapy

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