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Structure-guided discovery of cyclin-dependent kinase inhibitors.

Fischmann TO, Hruza A, Duca JS, Ramanathan L, Mayhood T, Windsor WT, Le HV, Guzi TJ, Dwyer MP, Paruch K, Doll RJ, Lees E, Parry D, Seghezzi W, Madison V
Biopolymers 89 372-9 (2008)
Related entries: 2r3f, 2r3g, 2r3h, 2r3i, 2r3j, 2r3k, 2r3l, 2r3m, 2r3n, 2r3o, 2r3p, 2r3q

Cited: 27 times
EuropePMC logo PMID: 17937404

Abstract

CDK2 inhibitors containing the related bicyclic heterocycles pyrazolopyrimidines and imidazopyrazines were discovered through high-throughput screening. Crystal structures of inhibitors with these bicyclic cores and two more related ones show that all but one have a common binding mode featuring two hydrogen bonds (H-bonds) to the backbone of the kinase hinge region. Even though ab initio computations indicated that the imidazopyrazine core would bind more tightly to the hinge, pyrazolopyrimidines gain an advantage in potency through participation of N4 in an H-bond network involving two catalytic residues and bridging water molecules. Further insight into inhibitor/CDK2 interactions was gained from analysis of additional crystal structures. Significant gains in potency were obtained by optimizing the fit of hydrophobic substituents to the gatekeeper region of the ATP binding site. The most potent inhibitors have good selectivity.

Articles - 2r3r mentioned but not cited (2)

  1. Rationalizing tight ligand binding through cooperative interaction networks. Kuhn B, Fuchs JE, Reutlinger M, Stahl M, Taylor NR. J Chem Inf Model 51 3180-3198 (2011)
  2. Mechanisms of Intervertebral Disc Degeneration Treatment with Deer Antlers Based on Network Pharmacology and Molecular Docking. Weng R, Lin H, Li Z, Chen D, Lin X, Zhang Z, Chen Q, Yao Y, Li W. Evid Based Complement Alternat Med 2022 8092848 (2022)


Reviews citing this publication (4)

  1. Cyclin-dependent kinase inhibitors: a survey of recent patent literature. Galons H, Oumata N, Meijer L. Expert Opin Ther Pat 20 377-404 (2010)
  2. Cyclin-dependent kinase inhibitors closer to market launch? Galons H, Oumata N, Gloulou O, Meijer L. Expert Opin Ther Pat 23 945-963 (2013)
  3. Recent advances in development of imidazo[1,2-a]pyrazines: synthesis, reactivity and their biological applications. Goel R, Luxami V, Paul K. Org Biomol Chem 13 3525-3555 (2015)
  4. Recent advances on CDK inhibitors: An insight by means of in silico methods. Tutone M, Almerico AM. Eur J Med Chem 142 300-315 (2017)

Articles citing this publication (21)

  1. Discovery of Dinaciclib (SCH 727965): A Potent and Selective Inhibitor of Cyclin-Dependent Kinases. Paruch K, Dwyer MP, Alvarez C, Brown C, Chan TY, Doll RJ, Keertikar K, Knutson C, McKittrick B, Rivera J, Rossman R, Tucker G, Fischmann T, Hruza A, Madison V, Nomeir AA, Wang Y, Kirschmeier P, Lees E, Parry D, Sgambellone N, Seghezzi W, Schultz L, Shanahan F, Wiswell D, Xu X, Zhou Q, James RA, Paradkar VM, Park H, Rokosz LR, Stauffer TM, Guzi TJ. ACS Med Chem Lett 1 204-208 (2010)
  2. The design and application of target-focused compound libraries. Harris CJ, Hill RD, Sheppard DW, Slater MJ, Stouten PF. Comb Chem High Throughput Screen 14 521-531 (2011)
  3. A novel approach of dynamic cross correlation analysis on molecular dynamics simulations and its application to Ets1 dimer-DNA complex. Kasahara K, Fukuda I, Nakamura H. PLoS One 9 e112419 (2014)
  4. Design, synthesis and inhibitory activities of naringenin derivatives on human colon cancer cells. Yoon H, Kim TW, Shin SY, Park MJ, Yong Y, Kim DW, Islam T, Lee YH, Jung KY, Lim Y. Bioorg Med Chem Lett 23 232-238 (2013)
  5. Identification of High-Affinity Inhibitors of Cyclin-Dependent Kinase 2 Towards Anticancer Therapy. Mohammad T, Batra S, Dahiya R, Baig MH, Rather IA, Dong JJ, Hassan I. Molecules 24 (2019)
  6. Binding studies and quantitative structure-activity relationship of 3-amino-1H-indazoles as inhibitors of GSK3β. Caballero J, Zilocchi S, Tiznado W, Collina S, Rossi D. Chem Biol Drug Des 78 631-641 (2011)
  7. Structure-based design and optimization of 2-aminothiazole-4-carboxamide as a new class of CHK1 inhibitors. Huang X, Cheng CC, Fischmann TO, Duca JS, Richards M, Tadikonda PK, Reddy PA, Zhao L, Siddiqui MA, Parry D, Davis N, Seghezzi W, Wiswell D, Shipps GW. Bioorg Med Chem Lett 23 2590-2594 (2013)
  8. GIANT: pattern analysis of molecular interactions in 3D structures of protein-small ligand complexes. Kasahara K, Kinoshita K. BMC Bioinformatics 15 12 (2014)
  9. When Does Chemical Elaboration Induce a Ligand To Change Its Binding Mode? Malhotra S, Karanicolas J. J Med Chem 60 128-145 (2017)
  10. Determination of potential inhibitors based on isatin derivatives against SARS-CoV-2 main protease (mpro): a molecular docking, molecular dynamics and structure-activity relationship studies. Badavath VN, Kumar A, Samanta PK, Maji S, Das A, Blum G, Jha A, Sen A. J Biomol Struct Dyn 1-19 (2020)
  11. Robust optimization of scoring functions for a target class. Seifert MH. J Comput Aided Mol Des 23 633-644 (2009)
  12. Flexible protein-ligand docking using the Fleksy protocol. Wagener M, Vlieg Jd, Nabuurs SB. J Comput Chem 33 1215-1217 (2012)
  13. Polyphony: superposition independent methods for ensemble-based drug discovery. Pitt WR, Montalvão RW, Blundell TL. BMC Bioinformatics 15 324 (2014)
  14. Haptic-driven, interactive drug design: implementing a GPU-based approach to evaluate the induced fit effect. Anthopoulos A, Pasqualetto G, Grimstead I, Brancale A. Faraday Discuss 169 323-342 (2014)
  15. Sampling Conformational Changes of Bound Ligands Using Nonequilibrium Candidate Monte Carlo and Molecular Dynamics. Sasmal S, Gill SC, Lim NM, Mobley DL. J Chem Theory Comput 16 1854-1865 (2020)
  16. Improving the Accuracy of Protein-Ligand Binding Mode Prediction Using a Molecular Dynamics-Based Pocket Generation Approach. Araki M, Iwata H, Ma B, Fujita A, Terayama K, Sagae Y, Ono F, Tsuda K, Kamiya N, Okuno Y. J Comput Chem 39 2679-2689 (2018)
  17. Pyrimidine-based pyrazoles as cyclin-dependent kinase 2 inhibitors: Design, synthesis, and biological evaluation. Vekariya MK, Vekariya RH, Brahmkshatriya PS, Shah NK. Chem Biol Drug Des 92 1683-1691 (2018)
  18. Design, synthesis, and molecular docking study of 3H-imidazole[4,5-c]pyridine derivatives as CDK2 inhibitors. Wu YZ, Ying HZ, Xu L, Cheng G, Chen J, Hu YZ, Liu T, Dong XW. Arch Pharm (Weinheim) 351 e1700381 (2018)
  19. Machine learning to estimate the local quality of protein crystal structures. Miyaguchi I, Sato M, Kashima A, Nakagawa H, Kokabu Y, Ma B, Matsumoto S, Tokuhisa A, Ohta M, Ikeguchi M. Sci Rep 11 23599 (2021)
  20. On the Value of Using 3D Shape and Electrostatic Similarities in Deep Generative Methods. Bolcato G, Heid E, Boström J. J Chem Inf Model 62 1388-1398 (2022)
  21. Synthesis, docking and anticancer activity of azo-linked hybrids of 1,3,4-thia-/oxadiazoles with cyclic imides. Bhatt P, Kumar M, Jha A. Mol Divers 22 827-840 (2018)


Related citations provided by authors (1)

  1. Versatile templates for the development of novel kinase inhibitors: Discovery of novel CDK inhibitors.. Dwyer MP, Paruch K, Alvarez C, Doll RJ, Keertikar K, Duca J, Fischmann TO, Hruza A, Madison V, Lees E, Parry D, Seghezzi W, Sgambellone N, Shanahan F, Wiswell D, Guzi TJ Bioorg Med Chem Lett 17 6216-9 (2007)

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