7-Azaindole: A Versatile Scaffold for Developing Kinase Inhibitors

Irie, Toshikazu; Sawa, Masaaki

doi:10.1248/cpb.c17-00380

Cited by 65 publications

(42 citation statements)

References 41 publications

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“…TRAIL, TRAIL receptors agonists (death receptors 4 and 5 agonists), and TRAIL mimics are shown as dream anticancer agents because they selectively target cancer cells sparing the normal cells . However, the challenge of resistance to these agents limits their clinical applications . The discovery that DAPK2 can sensitize the cells to TRAIL‐mediated apoptosis and induce the gene expression of DR 4/5 opens a new opportunity for small molecule TRAIL mimics and TRAIL receptor agonists with enhanced abilities against the rapidly developing resistance.…”

Section: Discussionmentioning

confidence: 99%

Death‐associated protein kinase (DAPK) family modulators: Current and future therapeutic outcomes

Farag

Roh

2018

Medicinal Research Reviews

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Serine/threonine kinases (STKs) represent the majority of discovered kinases to date even though a few Food and Drug Administration approved STKs inhibitors are reported. The third millennium came with the discovery of an important group of STKs that reshaped our understanding of several biological signaling pathways. This family was named death-associated protein kinase family (DAPK family). DAPKs comprise five members (DAPK1, DAPK2, DAPK3, DRAK1, and DRAK2) and belong to the calcium/calmodulin-dependent kinases domain. As time goes on, the list of biological functions of this family is constantly updated. The most extensively studied member is DAPK1 (based on the publications number and Protein Data Bank reported crystal structures) that plays fundamental biological roles depending on the cellular context. DAPK1 regulates apoptosis, autophagy, contributes to the pathogenesis of Alzheimer's disease, acts as a tumor suppressor, inhibits metastasis, mediates the body responses to viral infections, and regulates the synaptic plasticity and depression. For their biological roles, several DAPKs' modulators have been reported for treatment of many diseases as well as acting as probe compounds to facilitate the understanding of the biological functions elicited by this family. Despite that, the number of reported modulators is still limited and more research needs to be conducted on the discovery of novel strategies to activate or inhibit this family. In this report, we aim at drawing more attention to this family by reviewing the recent updates regarding the structure, biological roles, and regulation of this family. In addition, the small-molecule modulators of this family are reviewed in details with their potential therapeutic outcomes evaluated to help medicinal chemists develop more potent and selective possible drug candidates.

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Section: Discussionmentioning

confidence: 99%

Death‐associated protein kinase (DAPK) family modulators: Current and future therapeutic outcomes

Farag

Roh

2018

Medicinal Research Reviews

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“…Because of its outstanding ability to bind to the hinge region of multiple protein kinases, 7‐azaindole has been acknowledged as a privileged fragment against kinases, and therefore, it has been incorporated into many kinase inhibitors (Irie & Sawa, 2018). In an attempt to study their pharmacokinetic properties and potentially improve their pharmacological activity, Giles, Saiprabha, and Yeshna (2019) designed a series of 7‐azaindole‐chalcones and studied their docking interactions with B‐Raf kinase.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and evaluation of C3 substituted chalcone‐based derivatives of 7‐azaindole as protein kinase inhibitors

et al. 2020

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Chalcones are a group of naturally occurring or synthetic compounds which possess a wide range of biological activities. In this paper, a series of twenty-three 7-azaindole-chalcone hybrids (5a-w) were synthesized and evaluated as potential protein kinase inhibitors. Analyses of structure-activity relationships revealed that some of these compounds exhibit significant activity against Haspin kinase, with compounds 5f and 5q exhibiting IC 50 values of 0.47 and 0.41 µM, respectively. Furthermore, 5f also inhibits cyclin-dependent kinase 9 (CDK9/CyclinT) in a micromolar potency (IC 50 = 2.26 µM). This novel dual-target inhibitor is a promising lead for the development of chemopreventive/chemotherapeutic agents.

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“…7-Azaindole is a well-known hinge-binding element in kinase inhibition [1,2,3,4,5]. The N atom of the pyridine ring and the NH group of the pyrrole moiety of 7-azaindole serve as the hydrogen bond acceptor and donor, respectively, to make bidentate hydrogen bonds with the hinge region of the kinase.…”

Section: Introductionmentioning

confidence: 99%

Solvent-Free C-3 Coupling of Azaindoles with Cyclic Imines

2019

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By direct coupling 7-azaindole and cyclic imines, such as 3,4-dihydroisoquinoline, 6,7-dihydrothieno[3,2-c]pyridine, 3,4-dihydro-β-carboline, and 4,5-dihydro-3H-benz[c]azepine, new 3-substituted 7-azaindole derivatives have been synthesized. The reaction was extended to 4-azaindoles and 6-azaindoles, as electron-rich aromatic compounds. The lowest reactivity was observed in the case of C-3 substitution of 5-azaindole. In this case, the aza-Friedel-Crafts reaction took place by using 10 mol % of p-toluenesulfonic acid (p-TSA) as the catalyst. The role of the acid catalyst can be explained by the different pKa values of the azaindoles. All reactions were performed in solvent-free conditions by using both classical heating and microwave irradiation. In all cases, microwave heating proved to be more convenient to synthesize new C-3-substituted azaindole derivatives.

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7-Azaindole: A Versatile Scaffold for Developing Kinase Inhibitors

Cited by 65 publications

References 41 publications

Death‐associated protein kinase (DAPK) family modulators: Current and future therapeutic outcomes

Death‐associated protein kinase (DAPK) family modulators: Current and future therapeutic outcomes

Synthesis and evaluation of C3 substituted chalcone‐based derivatives of 7‐azaindole as protein kinase inhibitors

Solvent-Free C-3 Coupling of Azaindoles with Cyclic Imines

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