Design and synthesis of 7H-pyrrolo[2,3-d]pyrimidines as focal adhesion kinase inhibitors. Part 1

Choi, Ha-soon; Wang, Zhicheng; Richmond, Wendy; He, Xiaohui; Yang, Kunyong; Jiang, Tao; Karanewsky, Donald S.; Gu, Xiaoqiong; Zhou, Vicki; Liu, Yi; Che, Jianwei; Lee, Christian C.; Caldwell, Jeremy S.; Kanazawa, Takanori; Umemura, Ichiro; Matsuura, Naoko; Ohmori, Osamu; Honda, Toshiyuki; Gray, Nathanael S.; He, Yan

doi:10.1016/j.bmcl.2006.01.053

Cited by 55 publications

(32 citation statements)

References 21 publications

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“…Although other small molecules with FAK inhibitory activity have been described, they are either nonselective, thereby confounding data interpretation and utility, or have not been evaluated in cellular systems (33,34). The careful evaluation of pharmacokinetics and pharmacodynamics in vivo will be required to fully understand the role of FAK inhibition in the regulation of tumorigenesis and metastatic progression.…”

Section: Discussionmentioning

confidence: 99%

Cellular Characterization of a Novel Focal Adhesion Kinase Inhibitor

Slack‐Davis

Martin

Tilghman

et al. 2007

Journal of Biological Chemistry

440

447

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Focal adhesion kinase (FAK) is a member of a family of nonreceptor protein-tyrosine kinases that regulates integrin and growth factor signaling pathways involved in cell migrationThe ability of cells to respond appropriately to environmental cues is critical to maintaining cellular, tissue, and organism homeostasis. One such environmental cue is derived from cellular adhesion to the extracellular matrix. The loss of adhesiondependent cellular regulation can lead to increased cellular proliferation, decreased cell death, changes in cellular differentiation status, and altered cellular migratory capacity, all of which are critical components of cell carcinogenesis and metastatic progression.The FAK 4 family kinases (which include FAK and Pyk2) regulate cell adhesion, migration, and proliferation in a variety of cell types (for review see Refs. 1-3). Adhesion of cells to the extracellular matrix is mediated by heterodimeric transmembrane integrin receptors located within sites of close opposition to the underlying matrix called focal adhesions. Integrin engagement and clustering stimulates FAK phosphorylation on Tyr 397 , creating a high affinity binding site for Src and Src family kinases. The FAK⅐Src complex phosphorylates many components of the focal adhesion, resulting in changes in adhesion dynamics and the initiation of signaling cascades. In addition to FAK catalytic activity, FAK also functions as a scaffold to organize structural and signaling proteins within focal adhesions.The importance of FAK as a regulator of normal cellular function is underscored by the number of cancers reported to have alterations in FAK expression and/or activity, including colon, breast, thyroid, prostate, cervical, ovarian, head and neck, oral, liver, stomach, sarcoma, glioblastoma, and melanoma (4, 5). Additionally, alterations in FAK expression and/or activity have been associated with tumorigenesis and increased metastatic potential (4, 5). Currently, it is unclear how the catalytic and/or scaffolding function of FAK contributes to tumor progression. To date studies of FAK function have relied on the expression of dominant interfering mutants or elimination of FAK expression by genetic knock-out, antisense oligonucleotide expression, or small interfering RNA.Herein, we report the biochemical and cellular characterization of a novel small molecule inhibitor, PF-573,228 (here after referred to as PF-228), that targets FAK catalytic activity. The inhibitor interacts with FAK in the ATP-binding pocket and effectively blocks the catalytic activity of recombinant FAK protein or endogenous FAK expressed in a variety of normal and cancer cell lines. Treatment of cells with PF-228 blocked FAK phosphorylation on Tyr 397 and concomitantly reduced the tyrosine phosphorylation of paxillin, a recognized downstream effector of FAK signaling. Drug treatment of normal and cancer cells resulted in decreased cell migration and inhibited adhesion turnover, biological activities previously ascribed to FAK. Interestingly, inhibition of FAK activi...

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Section: Discussionmentioning

confidence: 99%

Cellular Characterization of a Novel Focal Adhesion Kinase Inhibitor

Slack‐Davis

Martin

Tilghman

et al. 2007

Journal of Biological Chemistry

440

447

View full text Add to dashboard Cite

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“…Pharmacologic blockade of FAK autophosphorylation reduces tumor growth in vivo(62) The FAK gene encodes a non-receptor tyrosine kinase that localizes at contact points of cells with extracellular matrix, and is activated by integrin (cell surface receptor) signaling. Recently Novartis Inc. developed FAK inhibitors down-regulation its kinase activity(63). The novel Novartis FAK inhibitor, TAE-226 recently was employed in brain cancer and effectively inhibited FAK signaling and caused apoptosis in these cells (64).…”

Section: Cell Adhesion To the Extracellular Membranementioning

confidence: 99%

Targeting Angiogenesis and the Tumor Microenvironment

Samples¹,

Willis²,

Klauber-DeMore³

2013

Surgical Oncology Clinics of North America

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Synopsis The role of the microenvironment during the initiation and progression of malignancy is appreciated to be of critical importance for improved molecular diagnostics and therapeutics. The tumor microenvironment is the product of a crosstalk between different cells types. Critical elements in the microenvironment include tumor associated fibroblasts, which provide an essential communication network via secretion of growth factors and chemokines, inducing an altered extracellular matrix (ECM), thereby providing additional oncogenic signals that enhance cancer-cell proliferation and invasion. Active contribution of tumor-associated stromal cells to cancer progression has been recognized. Stromal elements consist of the ECM, fibroblasts of various phenotypes, and a scaffold composed of immune and inflammatory cells, blood and lymph vessels, and nerves. This review will focus on therapeutic targets in the microenvironment related to tumor endothelium, tumor associated fibroblasts and the extracellular matrix.

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“…FAK is shown to be elevated in number of human cancers including melanoma [2,15] sarcomas [45], cervical carcinoma [22,29], prostate [34,42] colon, breast [4,7,20,31] and ovary [16,40]. Furthermore, increased dosage and occasional amplification of the region of chromosome 8q, that encodes the FAK gene, has been found in human tumors and tumor-derived cell lines of squamous cell carcinomas, lung, breast and colon [1].…”

Section: Fak and Its Expression In Cancermentioning

confidence: 99%

“…Small molecule inhibitors of FAK kinase activity have been recently published [6,7,18,19]. A number of 7H-pyrrolo [2,3d]pyrimidines displayed low to sub-micromolar inhibitory activities against focal adhesion kinase in vitro.…”

Section: Strategies For Fak Inhibition As Chemo-therapy Small Moleculmentioning

confidence: 99%

“…FAK has been implicated in controlling integrin and growth factor receptor mediated biological processes including cell motility, migration, apoptosis and cell survival. Recently, the structures of some small molecule inhibitors of FAK have been published [6,7,18,19]. Since FAK's discovery in early 1990's, a great deal of new information has been gained with regard to the biology of FAK and it's role in cellular processes.…”

Section: Introductionmentioning

confidence: 99%

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Role of Focal Adhesion Kinase in Human Cancer: A Potential Target for Drug Discovery

Han

McGonigal²

2007

ACAMC

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The focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that localizes to the points of cell contact with the extracellular matrix, called focal adhesions. FAK is involved in several cellular processes including invasion, motility, proliferation and apoptosis. In in vivo animal studies, FAK has been shown to contribute to tumor development and malignancy. Furthermore, FAK expression was shown to be elevated in a number of human cancers. Increased FAK expression and activity are correlated with malignant phenotype and poor prognosis in patients. Taken together, these studies suggest that FAK is a potentially good target for drug discovery. In this review, FAK and its relationship to cancer, as well as approaches to therapeutic intervention of FAK will be discussed.

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Design and synthesis of 7H-pyrrolo[2,3-d]pyrimidines as focal adhesion kinase inhibitors. Part 1

Cited by 55 publications

References 21 publications

Cellular Characterization of a Novel Focal Adhesion Kinase Inhibitor

Cellular Characterization of a Novel Focal Adhesion Kinase Inhibitor

Targeting Angiogenesis and the Tumor Microenvironment

Role of Focal Adhesion Kinase in Human Cancer: A Potential Target for Drug Discovery

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