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Discovery of a novel family of CDK inhibitors with the program LIDAEUS: structural basis for ligand-induced disordering of the activation loop.

Wu SY, McNae I, Kontopidis G, McClue SJ, McInnes C, Stewart KJ, Wang S, Zheleva DI, Marriage H, Lane DP, Taylor P, Fischer PM, Walkinshaw MD
Structure 11 399-410 (2003)
Related entries: 1pw2, 1pxj, 1pxk, 1pxl

Cited: 50 times
EuropePMC logo PMID: 12679018

Abstract

A family of 4-heteroaryl-2-amino-pyrimidine CDK2 inhibitor lead compounds was discovered with the new database-mining program LIDAEUS through in silico screening. Four compounds with IC(50) values ranging from 17 to 0.9 microM were selected for X-ray crystal analysis. Two distinct binding modes are observed, one of which resembles the hydrogen bonding pattern of bound ATP. In the second binding mode, the ligands trigger a conformational change in the activation T loop by inducing movement of Lys(33) and Asp(145) side chains. The family of molecules discovered provides an excellent starting point for the design and synthesis of tight binding inhibitors, which may lead to a new class of antiproliferative drugs.

Articles - 1pxi mentioned but not cited (4)

  1. In Silico Identification and In Vitro and In Vivo Validation of Anti-Psychotic Drug Fluspirilene as a Potential CDK2 Inhibitor and a Candidate Anti-Cancer Drug. Shi XN, Li H, Yao H, Liu X, Li L, Leung KS, Kung HF, Lu D, Wong MH, Lin MC. PLoS One 10 e0132072 (2015)
  2. Training a scoring function for the alignment of small molecules. Chan SL, Labute P. J Chem Inf Model 50 1724-1735 (2010)
  3. Ligand binding remodels protein side-chain conformational heterogeneity. Wankowicz SA, de Oliveira SH, Hogan DW, van den Bedem H, Fraser JS. Elife 11 e74114 (2022)
  4. A Free Web-Based Protocol to Assist Structure-Based Virtual Screening Experiments. Lagarde N, Goldwaser E, Pencheva T, Jereva D, Pajeva I, Rey J, Tuffery P, Villoutreix BO, Miteva MA. Int J Mol Sci 20 E4648 (2019)


Reviews citing this publication (11)

  1. Targeting polo-like kinase 1 for cancer therapy. Strebhardt K, Ullrich A. Nat Rev Cancer 6 321-330 (2006)
  2. Towards the development of universal, fast and highly accurate docking/scoring methods: a long way to go. Moitessier N, Englebienne P, Lee D, Lawandi J, Corbeil CR. Br J Pharmacol 153 Suppl 1 S7-26 (2008)
  3. Virtual screening strategies in drug discovery. McInnes C. Curr Opin Chem Biol 11 494-502 (2007)
  4. Computational toxicology in drug development. Muster W, Breidenbach A, Fischer H, Kirchner S, Müller L, Pähler A. Drug Discov Today 13 303-310 (2008)
  5. High-throughput docking as a source of novel drug leads. Alvarez JC. Curr Opin Chem Biol 8 365-370 (2004)
  6. Dysregulation of CDK8 and Cyclin C in tumorigenesis. Xu W, Ji JY. J Genet Genomics 38 439-452 (2011)
  7. Docking screens: right for the right reasons? Kolb P, Irwin JJ. Curr Top Med Chem 9 755-770 (2009)
  8. Structure-based development of target-specific compound libraries. Orry AJ, Abagyan RA, Cavasotto CN. Drug Discov Today 11 261-266 (2006)
  9. Selectivity and potency of cyclin-dependent kinase inhibitors. Sridhar J, Akula N, Pattabiraman N. AAPS J 8 E204-21 (2006)
  10. Ligand discovery and virtual screening using the program LIDAEUS. Taylor P, Blackburn E, Sheng YG, Harding S, Hsin KY, Kan D, Shave S, Walkinshaw MD. Br J Pharmacol 153 Suppl 1 S55-67 (2008)
  11. Inhibitors of Cyclin-Dependent Kinases: Types and Their Mechanism of Action. Łukasik P, Baranowska-Bosiacka I, Kulczycka K, Gutowska I. Int J Mol Sci 22 2806 (2021)

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  1. The FTMap family of web servers for determining and characterizing ligand-binding hot spots of proteins. Kozakov D, Grove LE, Hall DR, Bohnuud T, Mottarella SE, Luo L, Xia B, Beglov D, Vajda S. Nat Protoc 10 733-755 (2015)
  2. Inhibitors of Polo-like kinase reveal roles in spindle-pole maintenance. McInnes C, Mazumdar A, Mezna M, Meades C, Midgley C, Scaerou F, Carpenter L, Mackenzie M, Taylor P, Walkinshaw M, Fischer PM, Glover D. Nat Chem Biol 2 608-617 (2006)
  3. AADS--an automated active site identification, docking, and scoring protocol for protein targets based on physicochemical descriptors. Singh T, Biswas D, Jayaram B. J Chem Inf Model 51 2515-2527 (2011)
  4. Cyclin Dependent Kinase 9 Inhibitors for Cancer Therapy. Sonawane YA, Taylor MA, Napoleon JV, Rana S, Contreras JI, Natarajan A. J Med Chem 59 8667-8684 (2016)
  5. Sanjeevini: a freely accessible web-server for target directed lead molecule discovery. Jayaram B, Singh T, Mukherjee G, Mathur A, Shekhar S, Shekhar V. BMC Bioinformatics 13 Suppl 17 S7 (2012)
  6. Discovery and characterization of 2-anilino-4- (thiazol-5-yl)pyrimidine transcriptional CDK inhibitors as anticancer agents. Wang S, Griffiths G, Midgley CA, Barnett AL, Cooper M, Grabarek J, Ingram L, Jackson W, Kontopidis G, McClue SJ, McInnes C, McLachlan J, Meades C, Mezna M, Stuart I, Thomas MP, Zheleva DI, Lane DP, Jackson RC, Glover DM, Blake DG, Fischer PM. Chem Biol 17 1111-1121 (2010)
  7. REPLACE: a strategy for iterative design of cyclin-binding groove inhibitors. Andrews MJ, Kontopidis G, McInnes C, Plater A, Innes L, Cowan A, Jewsbury P, Fischer PM. Chembiochem 7 1909-1915 (2006)
  8. Structural determinants of CDK4 inhibition and design of selective ATP competitive inhibitors. McInnes C, Wang S, Anderson S, O'Boyle J, Jackson W, Kontopidis G, Meades C, Mezna M, Thomas M, Wood G, Lane DP, Fischer PM. Chem Biol 11 525-534 (2004)
  9. Insights into cyclin groove recognition: complex crystal structures and inhibitor design through ligand exchange. Kontopidis G, Andrews MJ, McInnes C, Cowan A, Powers H, Innes L, Plater A, Griffiths G, Paterson D, Zheleva DI, Lane DP, Green S, Walkinshaw MD, Fischer PM. Structure 11 1537-1546 (2003)
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  11. Differential binding of inhibitors to active and inactive CDK2 provides insights for drug design. Kontopidis G, McInnes C, Pandalaneni SR, McNae I, Gibson D, Mezna M, Thomas M, Wood G, Wang S, Walkinshaw MD, Fischer PM. Chem Biol 13 201-211 (2006)
  12. "Acceptor-donor-acceptor" motifs recognize the Watson-Crick, Hoogsteen and Sugar "donor-acceptor-donor" edges of adenine and adenosine-containing ligands. Denessiouk KA, Johnson MS. J Mol Biol 333 1025-1043 (2003)
  13. Comparative structural and functional studies of 4-(thiazol-5-yl)-2-(phenylamino)pyrimidine-5-carbonitrile CDK9 inhibitors suggest the basis for isotype selectivity. Hole AJ, Baumli S, Shao H, Shi S, Huang S, Pepper C, Fischer PM, Wang S, Endicott JA, Noble ME. J Med Chem 56 660-670 (2013)
  14. Fadraciclib (CYC065), a novel CDK inhibitor, targets key pro-survival and oncogenic pathways in cancer. Frame S, Saladino C, MacKay C, Atrash B, Sheldrake P, McDonald E, Clarke PA, Workman P, Blake D, Zheleva D. PLoS One 15 e0234103 (2020)
  15. Identification and characterization of fragment binding sites for allosteric ligand design using the site identification by ligand competitive saturation hotspots approach (SILCS-Hotspots). MacKerell AD, Jo S, Lakkaraju SK, Lind C, Yu W. Biochim Biophys Acta Gen Subj 1864 129519 (2020)
  16. Loop flexibility and solvent dynamics as determinants for the selective inhibition of cyclin-dependent kinase 4: comparative molecular dynamics simulation studies of CDK2 and CDK4. Park H, Yeom MS, Lee S. Chembiochem 5 1662-1672 (2004)
  17. The Flavonoid Metabolite 2,4,6-Trihydroxybenzoic Acid Is a CDK Inhibitor and an Anti-Proliferative Agent: A Potential Role in Cancer Prevention. Sankaranarayanan R, Valiveti CK, Kumar DR, Van Slambrouck S, Kesharwani SS, Seefeldt T, Scaria J, Tummala H, Bhat GJ. Cancers (Basel) 11 E427 (2019)
  18. Synthesis and biological activity of 2-anilino-4-(1H-pyrrol-3-yl) pyrimidine CDK inhibitors. Wang S, Wood G, Meades C, Griffiths G, Midgley C, McNae I, McInnes C, Anderson S, Jackson W, Mezna M, Yuill R, Walkinshaw M, Fischer PM. Bioorg Med Chem Lett 14 4237-4240 (2004)
  19. Transferable scoring function based on semiempirical quantum mechanical PM6-DH2 method: CDK2 with 15 structurally diverse inhibitors. Dobeš P, Fanfrlík J, Rezáč J, Otyepka M, Hobza P. J Comput Aided Mol Des 25 223-235 (2011)
  20. Discovery of a new class of inhibitors for the protein arginine deiminase type 4 (PAD4) by structure-based virtual screening. Teo CY, Shave S, Chor AL, Salleh AB, Rahman MB, Walkinshaw MD, Tejo BA. BMC Bioinformatics 13 Suppl 17 S4 (2012)
  21. Classical anticytokinins do not interact with cytokinin receptors but inhibit cyclin-dependent kinases. Spíchal L, Krystof V, Paprskárová M, Lenobel R, Styskala J, Binarová P, Cenklová V, De Veylder L, Inzé D, Kontopidis G, Fischer PM, Schmülling T, Strnad M. J Biol Chem 282 14356-14363 (2007)
  22. Peptide, Peptidomimetic, and Small-molecule Antagonists of the p53-HDM2 Protein-Protein Interaction. Fischer PM. Int J Pept Res Ther 12 3-19 (2006)
  23. Truncation and optimisation of peptide inhibitors of cyclin-dependent kinase 2-cyclin a through structure-guided design. Kontopidis G, Andrews MJ, McInnes C, Plater A, Innes L, Renachowski S, Cowan A, Fischer PM. ChemMedChem 4 1120-1128 (2009)
  24. Structure-based discovery of a family of synthetic cyclophilin inhibitors showing a cyclosporin-A phenotype in Caenorhabditis elegans. Yang Y, Moir E, Kontopidis G, Taylor P, Wear MA, Malone K, Dunsmore CJ, Page AP, Turner NJ, Walkinshaw MD. Biochem Biophys Res Commun 363 1013-1019 (2007)
  25. Aspirin metabolites 2,3‑DHBA and 2,5‑DHBA inhibit cancer cell growth: Implications in colorectal cancer prevention. Sankaranarayanan R, Valiveti CK, Dachineni R, Kumar DR, Lick T, Bhat GJ. Mol Med Rep 21 20-34 (2020)
  26. UFSRAT: Ultra-fast Shape Recognition with Atom Types--the discovery of novel bioactive small molecular scaffolds for FKBP12 and 11βHSD1. Shave S, Blackburn EA, Adie J, Houston DR, Auer M, Webster SP, Taylor P, Walkinshaw MD. PLoS One 10 e0116570 (2015)
  27. Identification of novel CDK2 inhibitors by a multistage virtual screening method based on SVM, pharmacophore and docking model. Liang JW, Wang MY, Wang S, Li SL, Li WQ, Meng FH. J Enzyme Inhib Med Chem 35 235-244 (2020)
  28. Inhibitor Selectivity for Cyclin-Dependent Kinase 7: A Structural, Thermodynamic, and Modelling Study. Hazel P, Kroll SH, Bondke A, Barbazanges M, Patel H, Fuchter MJ, Coombes RC, Ali S, Barrett AG, Freemont PS. ChemMedChem 12 372-380 (2017)
  29. Analogs of N'-hydroxy-N-(4H,5H-naphtho[1,2-d]thiazol-2-yl)methanimidamide inhibit Mycobacterium tuberculosis methionine aminopeptidases. Bhat S, Olaleye O, Meyer KJ, Shi W, Zhang Y, Liu JO. Bioorg Med Chem 20 4507-4513 (2012)
  30. Investigation of the flexibility of protein kinases implicated in the pathology of Alzheimer's disease. Mazanetz MP, Laughton CA, Fischer PM. Molecules 19 9134-9159 (2014)
  31. Drug targets for cell cycle dysregulators in leukemogenesis: in silico docking studies. Jayaraman A, Jamil K. PLoS One 9 e86310 (2014)
  32. Exponential repulsion improves structural predictability of molecular docking. Bazgier V, Berka K, Otyepka M, Banáš P. J Comput Chem 37 2485-2494 (2016)
  33. Efficient soluble expression of active recombinant human cyclin A2 mediated by E. coli molecular chaperones. Grigoroudis AI, McInnes C, Premnath PN, Kontopidis G. Protein Expr Purif 113 8-16 (2015)
  34. Structure of cyclin-dependent kinase 2 (CDK2) in complex with the specific and potent inhibitor CVT-313. Talapati SR, Nataraj V, Pothuganti M, Gore S, Ramachandra M, Antony T, More SS, Krishnamurthy NR. Acta Crystallogr F Struct Biol Commun 76 350-356 (2020)
  35. Congress CNIO cancer conference: targeted search for anticancer drugs. Fischer PM. Expert Opin Investig Drugs 12 1039-1044 (2003)


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