Synthesis and evaluation of FAK inhibitors with a 5-fluoro-7H-pyrrolo[2,3-d]pyrimidine scaffold as anti-hepatocellular carcinoma agents

Tan, Hanyi; Liu, Yue; Gong, Chaochao; Zhang, Jiawei; Huang, Jian; Zhang, Qian

doi:10.1016/j.ejmech.2021.113670

Cited by 12 publications

(4 citation statements)

References 40 publications

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“…Compound 18 showed potent inhibitory activity against focal adhesion kinase (FAK, IC 50 : 12 nM) and considerable antiproliferative activity (IC 50 : 2.39 and 10.07 µM, MTT assay) against YY8103 and SMMC7721 cancer cell lines. [32] Mechanistically, compound 18 influenced the phosphorylation levels of multiple signaling pathways, including downregulating the phosphorylation of downstream proteins associated with FAK, and upregulating the activity of several tumor suppressor genes. In the SMMC7721 xenografted mice model, compound 18 (TGI: 78.6% at a dose of 30 mg/kg by intraperitoneal injection) remarkably reduced tumor growth without causing significant weight loss or apparent toxicity, and the in vivo efficacy was superior to that of sorafenib (TGI: 45 ) cancer cells and could inhibit phosphorylation of the EGFR downstream mediators, block cancer cells in G0/G1 phase progression as well as induce apoptosis.…”

Section: Quinazoline Derivativesmentioning

confidence: 99%

Current scenario of fused pyrimidines with in vivo anticancer therapeutic potential

Xu,

Wang,

2024

Archiv der Pharmazie

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Cancer, characterized by uncontrolled cell growth and metastasis, is responsible for nearly one in six deaths and represents a severe threat to public health worldwide. Chemotherapy can substantially improve the quality of life and survival of patients with cancer, but anticancer chemotherapeutics are associated with a range of adverse effects. Moreover, almost all currently available anticancer chemotherapeutics could develop drug resistance over a period of time of application in cancer patients and ultimately lead to cancer relapse and death in 90% of patients, creating an urgent need to develop new anticancer agents. Fused pyrimidines trait the inextricable part of DNA and RNA and are vital in numerous biological processes. Fused pyrimidines can act on various biological cancer targets and have the potential to address drug resistance. In addition, more than 20 fused pyrimidines have already been approved for clinical treatment of different cancers and occupy a prominent place in the current therapeutic arsenal, revealing that fused pyrimidines are privileged scaffolds for the development of novel anticancer chemotherapeutics. The purpose of this review is to summarize the current scenario of fused pyrimidines with in vivo anticancer therapeutic potential along with their acute toxicity, metabolic profiles as well as pharmacokinetic properties, toxicity and mechanisms of action developed from 2020 to the present to facilitate further rational exploitation of more effective candidates.

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Section: Quinazoline Derivativesmentioning

confidence: 99%

Current scenario of fused pyrimidines with in vivo anticancer therapeutic potential

Xu,

Wang,

2024

Archiv der Pharmazie

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“…Results indicated that 20 , at 200 mg/kg dose, did not change rat body weight, and strongly decreased tumor growth. Furthermore, additional analyses suggested that 20 inhibited hepatocellular carcinoma cell (HCC) proliferation, blocking phosphorylation in FAK intracellular signalling [ 50 ].…”

Section: Fak Inhibitorsmentioning

confidence: 99%

The Development of FAK Inhibitors: A Five-Year Update

Spallarossa

Tasso

Russo

et al. 2022

IJMS

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Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase over-expressed in different solid cancers. In recent years, FAK has been recognized as a new target for the development of antitumor agents, useful to contrast tumor development and metastasis formation. To date, studies on the role of FAK and FAK inhibitors are of great interest for both pharmaceutical companies and academia. This review is focused on compounds able to block FAK with different potencies and with different mechanisms of action, that have appeared in the literature since 2017. Furthermore, new emerging PROTAC molecules have appeared in the literature. This summary could improve knowledge of new FAK inhibitors and provide information for future investigations, in particular, from a medicinal chemistry point of view.

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“…Recently, Tan and co-workers reported the synthesis of new 7 H -pyrrolo[2,3- d ] pyrimidines by adding a fluorine atom at position 5 of the core scaffold. 18 The reported derivatives possess potent FAK-blocking abilities and effectively suppress the growth of different cancer cells. 19…”

Section: Introductionmentioning

confidence: 99%

“…Recently, Tan and co-workers reported the synthesis of new 7Hpyrrolo [2,3-d] pyrimidines by adding a fluorine atom at position 5 of the core scaffold. 18 The reported derivatives possess potent FAK-blocking abilities and effectively suppress the growth of different cancer cells. 19 Computational drug design has been proven to be an extremely effective tool in drug discovery and design, saving time and costs by reducing the number of compounds that need to be evaluated and synthesized.…”

Section: Introductionmentioning

confidence: 99%

Computational investigation of novel pyrimidine derivatives as potent FAK inhibitorsvia3D-QSAR, molecular docking, molecular dynamics simulation and retrosynthesis

El Bahi,

Boutalaka,

El Alaouy

et al. 2023

New J. Chem.

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Synthesis and evaluation of FAK inhibitors with a 5-fluoro-7H-pyrrolo[2,3-d]pyrimidine scaffold as anti-hepatocellular carcinoma agents

Cited by 12 publications

References 40 publications

Current scenario of fused pyrimidines with in vivo anticancer therapeutic potential

Current scenario of fused pyrimidines with in vivo anticancer therapeutic potential

The Development of FAK Inhibitors: A Five-Year Update

Computational investigation of novel pyrimidine derivatives as potent FAK inhibitorsvia3D-QSAR, molecular docking, molecular dynamics simulation and retrosynthesis

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