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

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.2006.02.032

Cited by 56 publications

(41 citation statements)

References 10 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

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“…Pyrimidine and condensed pyrimidines are important classes of heterocyclic compounds that exhibit a broad spectrum of biological activities such as anticancer [6][7][8][9][10], antiviral [11], antibacterial [12,13], antioxidant [14,15], anxiolytic [16] and antidepressant activities [17]. Furthermore, they possess anti-inflammatory [18][19][20][21][22][23][24] and analgesic activities that are well documented in the literature [25][26][27]. The bicyclic pyrrolo [1,2-c]pyrimidine derivative I [28] and the tricyclic pyrimido [5,4-e]pyrrolo [1,2-c]pyrimidines IIa, b [29] and III [30], prepared in our laboratory, were found to have significant analgesic and anti-inflammatory activities, therefore, in continuation of these efforts, we have been interested in the synthesis of further bi-, tri-, and tetracyclic condensed pyrimidine derivatives retaining the pyrrolo [1,2-c]pyrimidine as a basic nucleus and evaluating their analgesic and anti-inflammatory activities.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, analgesic and anti-inflammatory activities evaluation of some bi-, tri- and tetracyclic condensed pyrimidines

Amin

Hanna

Abo-Youssef

et al. 2009

European Journal of Medicinal Chemistry

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“…Chemical equivalents for synthons for the incorporation of the 3-(3-aminophenyl)propionyl moiety represent important building blocks in the synthesis of biologically active compounds, e.g., GPR40 receptor agonists [1], focal adhesion kinase inhibitors [2], agonists of the EP 2 receptor [3], and inhibitors of protein-tyrosine phosphatase [4].…”

Section: Introductionmentioning

confidence: 99%

Short Synthesis of Ethyl 3‐(3‐aminophenyl)propanoate

Nagel

Radau

Link

2011

Archiv der Pharmazie

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A short and effective synthesis of ethyl 3-(3-aminophenyl)propanoate is presented, employing a tandem Knoevenagel condensation/alkylidene reduction of 3-nitrobenzaldehyde with Meldrum's acid in TEAF (triethylammonium formate) followed by reduction of the intermediate 3-(3-nitrophenyl)propanoic acid by stannous chloride in ethanol. The use of stannous chloride as the reducing agent in ethanol enabled the simultaneous esterification of the carboxylic acid. Thus, stannous chloride was acting simultaneously as a Lewis acid, which activates the carboxylic acid towards a nucleophilic attack by ethanol.

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

Cited by 56 publications

References 10 publications

Cellular Characterization of a Novel Focal Adhesion Kinase Inhibitor

Cellular Characterization of a Novel Focal Adhesion Kinase Inhibitor

Synthesis, analgesic and anti-inflammatory activities evaluation of some bi-, tri- and tetracyclic condensed pyrimidines

Short Synthesis of Ethyl 3‐(3‐aminophenyl)propanoate

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