Development of 6-substituted indolylquinolinones as potent Chek1 kinase inhibitors

Huang, Shaei; Garbaccio, R. M.; Fraley, Mark E.; Steen, Justin T.; Kreatsoulas, Constantine; Hartman, George D.; Stirdivant, Steve; Drakas, Bob; Rickert, Keith; Walsh, Eileen S.; Hamilton, Kelly; Buser, Carolyn A.; Hardwick, James C.H.; Mao, Xianzhi; Abrams, Marc; Beck, Steve; Tao, Weikang; Lobell, Rob; Sepp‐Lorenzino, Laura; Yan, Yong-Bin; Ikuta, Mari; Murphy, Joan Zugay; Sardana, Vinod; Munshi, Sanjeev; Kuo, Lawrence C.; Reilly, Michael; Mahan, Elizabeth

doi:10.1016/j.bmcl.2006.08.053

Cited by 35 publications

(19 citation statements)

References 20 publications

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“…As mentioned earlier, the synthesised PQs share a similar scaffold with some recently published Chk1 inhibitors 9 , 11 , 50 . Encouraged by the low IC 50 value of these reference structures (980–0.1 nM), we decided to give our compounds a chance to be tested as Chk1 inhibitors.…”

Section: Resultsmentioning

confidence: 72%

Synthesis and preliminary structure-activity relationship study of 2-aryl-2H-pyrazolo[4,3-c]quinolin-3-ones as potential checkpoint kinase 1 (Chk1) inhibitors

Malvacio

Cuzzolin

Sturlese

et al. 2017

Journal of Enzyme Inhibition and Medicinal Chemistry

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The serine-threonine checkpoint kinase 1 (Chk1) plays a critical role in the cell cycle arrest in response to DNA damage. In the last decade, Chk1 inhibitors have emerged as a novel therapeutic strategy to potentiate the anti-tumour efficacy of cytotoxic chemotherapeutic agents. In the search for new Chk1 inhibitors, a congeneric series of 2-aryl-2 H-pyrazolo[4,3-c]quinolin-3-one (PQ) was evaluated by in-vitro and in-silico approaches for the first time. A total of 30 PQ structures were synthesised in good to excellent yields using conventional or microwave heating, highlighting that 14 of them are new chemical entities. Noteworthy, in this preliminary study two compounds 4e2 and 4h2 have shown a modest but significant reduction in the basal activity of the Chk1 kinase. Starting from these preliminary results, we have designed the second generation of analogous in this class and further studies are in progress in our laboratories.

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Section: Resultsmentioning

confidence: 72%

Synthesis and preliminary structure-activity relationship study of 2-aryl-2H-pyrazolo[4,3-c]quinolin-3-ones as potential checkpoint kinase 1 (Chk1) inhibitors

Malvacio

Cuzzolin

Sturlese

et al. 2017

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…As outlined in our retrosynthetic plan (Figure 3) the synthesis of tetracyclic pyridone 1 can start with compounds such as ester 4/5 , which can be prepared from commercially available 2-iodoaniline (or 5-chloro-2-iodoaniline, Scheme 1) by iodo-vinyl exchange using phosphine-free, thermal Heck conditions9 in 86/92% yield. Treatment of the resulting ester 4/5 with aldehyde 6 (made from the commercially available ester)10 using modified Opatz conditions11, 12 provided the indole ester 7/8 in 73/68% yield.…”

Section: Resultsmentioning

confidence: 99%

Design and synthesis of a novel tyrosine kinase inhibitor template

Slavish

Jiang

Cui

et al. 2009

Bioorganic & Medicinal Chemistry

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We report the design and synthesis of an insulin receptor kinase family-targeted inhibitor template using the inhibitor conformation observed in an IGF1R/inhibitor co-crystal complex by application of a novel molecular design approach that we have recently published. The synthesis of the template involves a one pot Opatz cyclization reaction that provides a versatile indole ester in good yields. We also developed the required chemistry to elaborate this template with additional substituents and have used this chemistry to prepare some initial compounds that show selective inhibition of anaplastic lymphoma kinase (ALK). KeywordsAnaplastic lymphoma kinase; ALK; de novo ligand design; kinase template synthesis; insulin receptor kinase family; inhibitor design

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“…Among the 108 available X-ray structures for the hChk1, the following 20 ligand-protein complexes were selected for the docking benchmark (PDB IDs): 3TKH [27], 3TKI [27], 1ZYS [28], 4HYI [29], 4HYH [29], 3OT3 [30], 2HY0 [31], 2HXL [31], 2QHN [32], 3PA3 [33], 3PA4 [33], 3PA5 [33], 1ZLT [34], 3OT8 [35], 1NVR [36], 1NVS [36], 2YEX [37], 2YER [37], 2YDI [38], 2YM7 [39]. The structures were retrieved from the RCSB PDB database[13] and selected on the basis of their X-ray resolution (R, selection criterion = R < 1.8 Å).…”

Section: Methodsmentioning

confidence: 99%

DockBench: An Integrated Informatic Platform Bridging the Gap between the Robust Validation of Docking Protocols and Virtual Screening Simulations

et al. 2015

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Virtual screening (VS) is a computational methodology that streamlines the drug discovery process by reducing costs and required resources through the in silico identification of potential drug candidates. Structure-based VS (SBVS) exploits knowledge about the three-dimensional (3D) structure of protein targets and uses the docking methodology as search engine for novel hits. The success of a SBVS campaign strongly depends upon the accuracy of the docking protocol used to select the candidates from large chemical libraries.The identification of suitable protocols is therefore a crucial step in the setup of SBVS experiments. Carrying out extensive benchmark studies, however, is usually a tangled task that requires users' proficiency in handling different file formats and philosophies at the basis of the plethora of existing software packages. We present here DockBench 1.0, a platform available free of charge that eases the pipeline by automating the entire procedure, from docking benchmark to VS setups. In its current implementation, DockBench 1.0 OPEN ACCESSMolecules 2015, 20 9978 handles seven docking software packages and offers the possibility to test up to seventeen different protocols. The main features of our platform are presented here and the results of the benchmark study of human Checkpoint kinase 1 (hChk1) are discussed as validation test.

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Development of 6-substituted indolylquinolinones as potent Chek1 kinase inhibitors

Cited by 35 publications

References 20 publications

Synthesis and preliminary structure-activity relationship study of 2-aryl-2H-pyrazolo[4,3-c]quinolin-3-ones as potential checkpoint kinase 1 (Chk1) inhibitors

Synthesis and preliminary structure-activity relationship study of 2-aryl-2H-pyrazolo[4,3-c]quinolin-3-ones as potential checkpoint kinase 1 (Chk1) inhibitors

Design and synthesis of a novel tyrosine kinase inhibitor template

DockBench: An Integrated Informatic Platform Bridging the Gap between the Robust Validation of Docking Protocols and Virtual Screening Simulations

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