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Specific inhibition of CK2α from an anchor outside the active site.

Brear P, De Fusco C, Hadje Georgiou K, Francis-Newton NJ, Stubbs CJ, Sore HF, Venkitaraman AR, Abell C, Spring DR, Hyvönen M
Chem Sci 7 6839-6845 (2016)
Related entries: 5cs6, 5csh, 5csp, 5csv, 5cu3, 5cu4, 5cu6, 5cvf, 5cvg, 5cvh

Cited: 26 times
EuropePMC logo PMID: 28451126

Abstract

The development of selective inhibitors of protein kinases is challenging because of the significant conservation of the ATP binding site. Here, we describe a new mechanism by which the protein kinase CK2α can be selectively inhibited using features outside the ATP site. We have identified a new binding site for small molecules on CK2α adjacent to the ATP site and behind the αD loop, termed the αD pocket. An elaborated fragment anchored in this site has been linked with a low affinity fragment binding in the ATP site, creating a novel and selective inhibitor (CAM4066) that binds CK2α with a Kd of 320 nM and shows significantly improved selectivity compared to other CK2α inhibitors. CAM4066 shows target engagement in several cell lines and similar potency to clinical trial candidate CX4945. Our data demonstrate that targeting a poorly conserved, cryptic pocket allows inhibition of CK2α via a novel mechanism, enabling the development of a new generation of selective CK2α inhibitors.

Articles - 5clp mentioned but not cited (6)

  1. Fragment Hits: What do They Look Like and How do They Bind? Giordanetto F, Jin C, Willmore L, Feher M, Shaw DE. J Med Chem 62 3381-3394 (2019)
  2. Specific inhibition of CK2α from an anchor outside the active site. Brear P, De Fusco C, Hadje Georgiou K, Francis-Newton NJ, Stubbs CJ, Sore HF, Venkitaraman AR, Abell C, Spring DR, Hyvönen M. Chem Sci 7 6839-6845 (2016)
  3. 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)
  4. 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)
  5. 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)
  6. 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)


Reviews citing this publication (3)

  1. 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)
  2. 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)
  3. 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 (17)

  1. Cell-based screen identifies a new potent and highly selective CK2 inhibitor for modulation of circadian rhythms and cancer cell growth. Oshima T, Niwa Y, Kuwata K, Srivastava A, Hyoda T, Tsuchiya Y, Kumagai M, Tsuyuguchi M, Tamaru T, Sugiyama A, Ono N, Zolboot N, Aikawa Y, Oishi S, Nonami A, Arai F, Hagihara S, Yamaguchi J, Tama F, Kunisaki Y, Yagita K, Ikeda M, Kinoshita T, Kay SA, Itami K, Hirota T. Sci Adv 5 eaau9060 (2019)
  2. 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)
  3. Efficient development of stable and highly functionalised peptides targeting the CK2α/CK2β protein-protein interaction. Iegre J, Brear P, Baker DJ, Tan YS, Atkinson EL, Sore HF, O' Donovan DH, Verma CS, Hyvönen M, Spring DR. Chem Sci 10 5056-5063 (2019)
  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. Conformational dynamics of human protein kinase CK2α and its effect on function and inhibition. Srivastava A, Hirota T, Irle S, Tama F. Proteins 86 344-353 (2018)
  6. Diacritic Binding of an Indenoindole Inhibitor by CK2α Paralogs Explored by a Reliable Path to Atomic Resolution CK2α' Structures. Lindenblatt D, Nickelsen A, Applegate VM, Hochscherf J, Witulski B, Bouaziz Z, Marminon C, Bretner M, Le Borgne M, Jose J, Niefind K. ACS Omega 4 5471-5478 (2019)
  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. Discovery of holoenzyme-disrupting chemicals as substrate-selective CK2 inhibitors. Kufareva I, Bestgen B, Brear P, Prudent R, Laudet B, Moucadel V, Ettaoussi M, Sautel CF, Krimm I, Engel M, Filhol O, Borgne ML, Lomberget T, Cochet C, Abagyan R. Sci Rep 9 15893 (2019)
  9. Divergent response of homologous ATP sites to stereospecific ligand fluorination for selectivity enhancement. Patel AR, Hardianto A, Ranganathan S, Liu F. Org Biomol Chem 15 1570-1574 (2017)
  10. 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)
  11. 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)
  12. 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)
  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. Mechanism of CK2 Inhibition by a Ruthenium-Based Polyoxometalate. Fabbian S, Giachin G, Bellanda M, Borgo C, Ruzzene M, Spuri G, Campofelice A, Veneziano L, Bonchio M, Carraro M, Battistutta R. Front Mol Biosci 9 906390 (2022)
  15. Structural analysis of fungal pathogenicity-related casein kinase α subunit, Cka1, in the human fungal pathogen Cryptococcus neoformans. Ong BX, Yoo Y, Han MG, Park JB, Choi MK, Choi Y, Shin JS, Bahn YS, Cho HS. Sci Rep 9 14398 (2019)
  16. Chemical proteomics reveals the target landscape of 1,000 kinase inhibitors. Reinecke M, Brear P, Vornholz L, Berger BT, Seefried F, Wilhelm S, Samaras P, Gyenis L, Litchfield DW, Médard G, Müller S, Ruland J, Hyvönen M, Wilhelm M, Kuster B. Nat Chem Biol (2023)
  17. Development of small cyclic peptides targeting the CK2α/β interface. Atkinson EL, Iegre J, D'Amore C, Brear P, Salvi M, Hyvönen M, Spring DR. Chem Commun (Camb) 58 4791-4794 (2022)


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