2vtp › Citations

Identification of N-(4-piperidinyl)-4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxamide (AT7519), a novel cyclin dependent kinase inhibitor using fragment-based X-ray crystallography and structure based drug design.

Wyatt PG, Woodhead AJ, Berdini V, Boulstridge JA, Carr MG, Cross DM, Davis DJ, Devine LA, Early TR, Feltell RE, Lewis EJ, McMenamin RL, Navarro EF, O'Brien MA, O'Reilly M, Reule M, Saxty G, Seavers LC, Smith DM, Squires MS, Trewartha G, Walker MT, Woolford AJ
J Med Chem 51 4986-99 (2008)
Related entries: 2vta, 2vth, 2vti, 2vtj, 2vtl, 2vtm, 2vtn, 2vto, 2vtq, 2vtr, 2vts, 2vtt, 2vu3

Cited: 123 times
EuropePMC logo PMID: 18656911

Abstract

The application of fragment-based screening techniques to cyclin dependent kinase 2 (CDK2) identified multiple (>30) efficient, synthetically tractable small molecule hits for further optimization. Structure-based design approaches led to the identification of multiple lead series, which retained the key interactions of the initial binding fragments and additionally explored other areas of the ATP binding site. The majority of this paper details the structure-guided optimization of indazole (6) using information gained from multiple ligand-CDK2 cocrystal structures. Identification of key binding features for this class of compounds resulted in a series of molecules with low nM affinity for CDK2. Optimisation of cellular activity and characterization of pharmacokinetic properties led to the identification of 33 (AT7519), which is currently being evaluated in clinical trials for the treatment of human cancers.

Reviews - 2vtp mentioned but not cited (1)

  1. Lessons from Hot Spot Analysis for Fragment-Based Drug Discovery. Hall DR, Kozakov D, Whitty A, Vajda S. Trends Pharmacol. Sci. 36 724-736 (2015)

Articles - 2vtp mentioned but not cited (8)

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  3. Structure-based predictions of activity cliffs. Husby J, Bottegoni G, Kufareva I, Abagyan R, Cavalli A. J Chem Inf Model 55 1062-1076 (2015)
  4. Pharmacophore-based virtual screening, synthesis, biological evaluation, and molecular docking study of novel pyrrolizines bearing urea/thiourea moieties with potential cytotoxicity and CDK inhibitory activities. Shawky AM, Ibrahim NA, Abourehab MAS, Abdalla AN, Gouda AM. J Enzyme Inhib Med Chem 36 15-33 (2021)
  5. Discovery of thienoquinolone derivatives as selective and ATP non-competitive CDK5/p25 inhibitors by structure-based virtual screening. Chatterjee A, Cutler SJ, Doerksen RJ, Khan IA, Williamson JS. Bioorg. Med. Chem. 22 6409-6421 (2014)
  6. Benchmark Sets for Binding Hot Spot Identification in Fragment-Based Ligand Discovery. Wakefield AE, Yueh C, Beglov D, Castilho MS, Kozakov D, Keserű GM, Whitty A, Vajda S. J Chem Inf Model 60 6612-6623 (2020)
  7. In Silico Approach Using Free Software to Optimize the Antiproliferative Activity and Predict the Potential Mechanism of Action of Pyrrolizine-Based Schiff Bases. Almalki FA, Abdalla AN, Shawky AM, El Hassab MA, Gouda AM. Molecules 26 4002 (2021)
  8. A Benzothiazole Derivative (5g) Induces DNA Damage And Potent G2/M Arrest In Cancer Cells. Hegde M, Vartak SV, Kavitha CV, Ananda H, Prasanna DS, Gopalakrishnan V, Choudhary B, Rangappa KS, Raghavan SC. Sci Rep 7 2533 (2017)


Reviews citing this publication (32)

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