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A fragment-based approach leading to the discovery of a novel binding site and the selective CK2 inhibitor CAM4066.

De Fusco C, Brear P, Iegre J, Georgiou KH, Sore HF, Hyvönen M, Spring DR
Bioorg Med Chem 25 3471-3482 (2017)
Related entries: 5ct0, 5ctp, 5cu0, 5cu2, 5cx9, 5mmf, 5mmr, 5mo5, 5mo7, 5mo8, 5mod, 5moe, 5moh, 5mot, 5mov, 5mow, 5mp8, 5mpj

Cited: 19 times
EuropePMC logo PMID: 28495381

Abstract

Recently we reported the discovery of a potent and selective CK2α inhibitor CAM4066. This compound inhibits CK2 activity by exploiting a pocket located outside the ATP binding site (αD pocket). Here we describe in detail the journey that led to the discovery of CAM4066 using the challenging fragment linking strategy. Specifically, we aimed to develop inhibitors by linking a high-affinity fragment anchored in the αD site to a weakly binding warhead fragment occupying the ATP site. Moreover, we describe the remarkable impact that molecular modelling had on the development of this novel chemical tool. The work described herein shows potential for the development of a novel class of CK2 inhibitors.

Articles - 5mo6 mentioned but not cited (1)

  1. A fragment-based approach leading to the discovery of a novel binding site and the selective CK2 inhibitor CAM4066. De Fusco C, Brear P, Iegre J, Georgiou KH, Sore HF, Hyvönen M, Spring DR. Bioorg Med Chem 25 3471-3482 (2017)


Reviews citing this publication (4)

  1. In silico Strategies to Support Fragment-to-Lead Optimization in Drug Discovery. de Souza Neto LR, Moreira-Filho JT, Neves BJ, Maidana RLBR, Guimarães ACR, Furnham N, Andrade CH, Silva FP. Front Chem 8 93 (2020)
  2. Targeting Protein Kinases in Blood Cancer: Focusing on CK1α and CK2. Spinello Z, Fregnani A, Quotti Tubi L, Trentin L, Piazza F, Manni S. Int J Mol Sci 22 3716 (2021)
  3. Downfalls of Chemical Probes Acting at the Kinase ATP-Site: CK2 as a Case Study. Atkinson EL, Iegre J, Brear PD, Zhabina EA, Hyvönen M, Spring DR. Molecules 26 1977 (2021)
  4. Recent Advances in the Discovery of CK2 Allosteric Inhibitors: From Traditional Screening to Structure-Based Design. Chen X, Li C, Wang D, Chen Y, Zhang N. Molecules 25 E870 (2020)

Articles citing this publication (14)

  1. Second-generation CK2α inhibitors targeting the αD pocket. Iegre J, Brear P, De Fusco C, Yoshida M, Mitchell SL, Rossmann M, Carro L, Sore HF, Hyvönen M, Spring DR. Chem Sci 9 3041-3049 (2018)
  2. Novel non-ATP competitive small molecules targeting the CK2 α/β interface. Brear P, North A, Iegre J, Hadje Georgiou K, Lubin A, Carro L, Green W, Sore HF, Hyvönen M, Spring DR. Bioorg Med Chem 26 3016-3020 (2018)
  3. Alternaria toxins as casein kinase 2 inhibitors and possible consequences for estrogenicity: a hybrid in silico/in vitro study. Aichinger G, Dellafiora L, Pantazi F, Del Favero G, Galaverna G, Dall'Asta C, Marko D. Arch Toxicol 94 2225-2237 (2020)
  4. 2-Aminothiazole Derivatives as Selective Allosteric Modulators of the Protein Kinase CK2. 1. Identification of an Allosteric Binding Site. Bestgen B, Krimm I, Kufareva I, Kamal AAM, Seetoh WG, Abell C, Hartmann RW, Abagyan R, Cochet C, Le Borgne M, Engel M, Lomberget T. J Med Chem 62 1803-1816 (2019)
  5. 2-Aminothiazole Derivatives as Selective Allosteric Modulators of the Protein Kinase CK2. 2. Structure-Based Optimization and Investigation of Effects Specific to the Allosteric Mode of Action. Bestgen B, Kufareva I, Seetoh W, Abell C, Hartmann RW, Abagyan R, Le Borgne M, Filhol O, Cochet C, Lomberget T, Engel M. J Med Chem 62 1817-1836 (2019)
  6. Demonstration of the utility of DOS-derived fragment libraries for rapid hit derivatisation in a multidirectional fashion. Kidd SL, Fowler E, Reinhardt T, Compton T, Mateu N, Newman H, Bellini D, Talon R, McLoughlin J, Krojer T, Aimon A, Bradley A, Fairhead M, Brear P, Díaz-Sáez L, McAuley K, Sore HF, Madin A, O'Donovan DH, Huber KVM, Hyvönen M, von Delft F, Dowson CG, Spring DR. Chem Sci 11 10792-10801 (2020)
  7. Proposed Allosteric Inhibitors Bind to the ATP Site of CK2α. Brear P, Ball D, Stott K, D'Arcy S, Hyvönen M. J Med Chem 63 12786-12798 (2020)
  8. Unexpected Binding Mode of a Potent Indeno[1,2-b]indole-Type Inhibitor of Protein Kinase CK2 Revealed by Complex Structures with the Catalytic Subunit CK2α and Its Paralog CK2α'. Hochscherf J, Lindenblatt D, Witulski B, Birus R, Aichele D, Marminon C, Bouaziz Z, Le Borgne M, Jose J, Niefind K. Pharmaceuticals (Basel) 10 E98 (2017)
  9. From a MMP2/CK2 multitarget approach to the identification of potent and selective MMP13 inhibitors. Pastor M, Zapico JM, Coderch C, Maslyk M, Panchuk R, de Pascual-Teresa B, Ramos A. Org Biomol Chem 17 916-929 (2019)
  10. Identification and Biological Evaluation of CK2 Allosteric Fragments through Structure-Based Virtual Screening. Li C, Zhang X, Zhang N, Zhou Y, Sun G, Zhao L, Zhong R. Molecules 25 E237 (2020)
  11. Insights into the Impact of Linker Flexibility and Fragment Ionization on the Design of CK2 Allosteric Inhibitors: Comparative Molecular Dynamics Simulation Studies. Zhou Y, Zhang N, Qi X, Tang S, Sun G, Zhao L, Zhong R, Peng Y. Int J Mol Sci 19 E111 (2018)
  12. Synthesis and biological evaluations of a series of calycanthaceous analogues as antifungal agents. Zheng S, Zhu R, Tang B, Chen L, Bai H, Zhang J. Nat Prod Res 35 1816-1824 (2021)
  13. Crystal structure of the Rho-associated coiled-coil kinase 2 inhibitor belumosudil bound to CK2α. Brear P, Hyvönen M. Acta Crystallogr F Struct Biol Commun 78 348-353 (2022)
  14. A fragment-based approach leading to the discovery of inhibitors of CK2α with a novel mechanism of action. Brear P, De Fusco C, Atkinson EL, Iegre J, Francis-Newton NJ, Venkitaraman AR, Hyvönen M, Spring DR. RSC Med Chem 13 1420-1426 (2022)


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