Design, synthesis, biological evaluation and molecular docking study of novel thieno[3,2-d]pyrimidine derivatives as potent FAK inhibitors

Wang, Ruifeng; Yu, Sijia; Zhao, Xiangxin; Chen, Yixuan; Yang, Bowen; Wu, Tianxiao; Hao, Chenzhou; Cheng, Maosheng

doi:10.1016/j.ejmech.2019.112024

Cited by 39 publications

(34 citation statements)

References 28 publications

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“…The water-soluble 'tail' of the piperidine moiety points towards the solvent by forming a hydrogen bond with Cys427, located at the edge of the active pocket, confirming that the piperidine-4-yl moiety is an important contributor to FAK inhibition. These results indicated that 2,7-disubstituted-thieno[3,2-d] pyrimidine derivatives serve as a new class of FAK inhibitors that can be studied extensively for development as anticancer agents (Wang et al, 2020). Many groups evaluated different pyrimidine scaffolds along with a series of analogues for cytotoxic activity on several cancer cell lines along with FAK inhibitory activity.…”

Section: Pyrimidine Analoguesmentioning

confidence: 99%

Focal adhesion kinase—An emerging viable target in cancer and development of focal adhesion kinase inhibitors

Chauhan¹,

Khan

2020

Chem Biol Drug Des

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Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase located at the extracellular matrix cell adhesion site. This kinase mediates downstream signalling cascades on the cell-extracellular matrix of integrins, cytokine receptors, growth factor receptors and G-protein-coupled receptors. Several studies have suggested the importance of FAK in cancer cell adhesion, motility, proliferation and survival and is over-expressed in cancer cells. There is a growing body of evidence indicating involvement of FAK-mediated signalling and functions in development of tumour cells, making FAK an emerging viable therapeutic target. There is substantial research impetus on development of small molecule FAK inhibitors that impact and inhibit the downstream pathways of FAK, subsequently modulating cancer progression and survival. A variety of scaffolds including hybrid scaffolds have been designed and synthesized with some translating into clinical trials. In addition to the reduction of metastasis and angiogenesis, these inhibitors are effective in inducing tumour cell apoptosis. In this paper, we provide an overview of FAK and analysis of design, synthesis and structure-activity relationship of small molecule FAK inhibitors reported till date. We have discussed FAK inhibitors in clinical trials and highlighted future prospects in the development of FAK inhibitors to augment the armamentarium of cancer therapeutics.

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Section: Pyrimidine Analoguesmentioning

confidence: 99%

Focal adhesion kinase—An emerging viable target in cancer and development of focal adhesion kinase inhibitors

Chauhan¹,

Khan

2020

Chem Biol Drug Des

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“…Antiproliferative activity of the most active dihydropyrimidinone conjugate 43a.Thieno[3,2-d]pyrimidine analogs 44 were prepared and screened for antiproliferative and focal adhesion kinase (FAK) inhibitory activities[103]. Among them, the fluoro-substituted derivative 44a exhibited significant activity against U-87MG, A-549 and MDA-MB-231 cells with IC50 values of 0.16, 0.27 and 0.19 M respectively (Figure 51).…”

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confidence: 99%

A Review on Recent Advances in Nitrogen-Containing Molecules and Their Biological Applications

et al. 2020

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The analogs of nitrogen-based heterocycles occupy an exclusive position as a valuable source of therapeutic agents in medicinal chemistry. More than 75% of drugs approved by the FDA and currently available in the market are nitrogen-containing heterocyclic moieties. In the forthcoming decade, a much greater share of new nitrogen-based pharmaceuticals is anticipated. Many new nitrogen-based heterocycles have been designed. The number of novel N-heterocyclic moieties with significant physiological properties and promising applications in medicinal chemistry is ever-growing. In this review, we consolidate the recent advances on novel nitrogen-containing heterocycles and their distinct biological activities, reported over the past one year (2019 to early 2020). This review highlights the trends in the use of nitrogen-based moieties in drug design and the development of different potent and competent candidates against various diseases.

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“…Zhao et al, miming the bioactive conformation of the well-known diaminopyrimidine motif and using a cyclization strategy, synthesized a large series of 7 H -pyrrolo[2,3- d ]pyrimidines as Fak inhibitors. Very recently, they obtained new 2,7-disubstituted-thieno[3,2- d ]pyrimidine compounds by isosteric replacement of a pyrrole nucleus by a thiophene one [ 18 ], the most relevant being 1 ( Figure 5 ), which showed an IC 50 value of 28.2 nM in an enzymatic assay and displayed stronger potency than the reference compound TAE-226 in different biological assays.…”

Section: New Insight In Fak Inhibitorsmentioning

confidence: 99%

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes–7

et al. 2020

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Design, synthesis, biological evaluation and molecular docking study of novel thieno[3,2-d]pyrimidine derivatives as potent FAK inhibitors

Cited by 39 publications

References 28 publications

Focal adhesion kinase—An emerging viable target in cancer and development of focal adhesion kinase inhibitors

Focal adhesion kinase—An emerging viable target in cancer and development of focal adhesion kinase inhibitors

A Review on Recent Advances in Nitrogen-Containing Molecules and Their Biological Applications

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes–7

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