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Aminopyrazine inhibitors binding to an unusual inactive conformation of the mitotic kinase Nek2: SAR and structural characterization.

Whelligan DK, Solanki S, Taylor D, Thomson DW, Cheung KM, Boxall K, Mas-Droux C, Barillari C, Burns S, Grummitt CG, Collins I, van Montfort RL, Aherne GW, Bayliss R, Hoelder S
J Med Chem 53 7682-98 (2010)
Related entries: 2xk3, 2xk4, 2xk7, 2xk8, 2xkc, 2xkd, 2xke, 2xkf

Cited: 30 times
EuropePMC logo PMID: 20936789

Abstract

We report herein the first systematic exploration of inhibitors of the mitotic kinase Nek2. Starting from HTS hit aminopyrazine 2, compounds with improved activity were identified using structure-based design. Our structural biology investigations reveal two notable observations. First, 2 and related compounds bind to an unusual, inactive conformation of the kinase which to the best of our knowledge has not been reported for other types of kinase inhibitors. Second, a phenylalanine residue at the center of the ATP pocket strongly affects the ability of the inhibitor to bind to the protein. The implications of these observations are discussed, and the work described here defines key features for potent and selective Nek2 inhibition, which will aid the identification of more advanced inhibitors of Nek2.

Articles - 2xk6 mentioned but not cited (2)

  1. Aminopyrazine inhibitors binding to an unusual inactive conformation of the mitotic kinase Nek2: SAR and structural characterization. Whelligan DK, Solanki S, Taylor D, Thomson DW, Cheung KM, Boxall K, Mas-Droux C, Barillari C, Burns S, Grummitt CG, Collins I, van Montfort RL, Aherne GW, Bayliss R, Hoelder S. J Med Chem 53 7682-7698 (2010)
  2. Multiscale approach to the determination of the photoactive yellow protein signaling state ensemble. A Rohrdanz M, Zheng W, Lambeth B, Vreede J, Clementi C. PLoS Comput Biol 10 e1003797 (2014)


Reviews citing this publication (11)

  1. Cell cycle regulation by the NEK family of protein kinases. Fry AM, O'Regan L, Sabir SR, Bayliss R. J Cell Sci 125 4423-4433 (2012)
  2. CEP proteins: the knights of centrosome dynasty. Kumar A, Rajendran V, Sethumadhavan R, Purohit R. Protoplasma 250 965-983 (2013)
  3. Targeting NEK2 as a promising therapeutic approach for cancer treatment. Fang Y, Zhang X. Cell Cycle 15 895-907 (2016)
  4. On the molecular mechanisms of mitotic kinase activation. Bayliss R, Fry A, Haq T, Yeoh S. Open Biol 2 120136 (2012)
  5. Iron-Catalyzed Cross-Couplings in the Synthesis of Pharmaceuticals: In Pursuit of Sustainability. Piontek A, Bisz E, Szostak M. Angew Chem Int Ed Engl 57 11116-11128 (2018)
  6. The expanding utility of continuous flow hydrogenation. Cossar PJ, Hizartzidis L, Simone MI, McCluskey A, Gordon CP. Org Biomol Chem 13 7119-7130 (2015)
  7. Therapeutic melting pot of never in mitosis gene a related kinase 2 (Nek2): a perspective on Nek2 as an oncology target and recent advancements in Nek2 small molecule inhibition. Frett B, Brown RV, Ma M, Hu W, Han H, Li HY. J Med Chem 57 5835-5844 (2014)
  8. The structural mechanisms that underpin mitotic kinase activation. Dodson CA, Haq T, Yeoh S, Fry AM, Bayliss R. Biochem Soc Trans 41 1037-1041 (2013)
  9. In depth analysis of kinase cross screening data to identify chemical starting points for inhibition of the Nek family of kinases. Wells CI, Kapadia NR, Couñago RM, Drewry DH. Medchemcomm 9 44-66 (2018)
  10. Nek2 Kinase Signaling in Malaria, Bone, Immune and Kidney Disorders to Metastatic Cancers and Drug Resistance: Progress on Nek2 Inhibitor Development. Dana D, Das T, Choi A, Bhuiyan AI, Das TK, Talele TT, Pathak SK. Molecules 27 347 (2022)
  11. The hunt for antimitotic agents: an overview of structure-based design strategies. Dube D, Tiwari P, Kaur P. Expert Opin Drug Discov 11 579-597 (2016)

Articles citing this publication (17)

  1. Enantioselective cyanation of benzylic C-H bonds via copper-catalyzed radical relay. Zhang W, Wang F, McCann SD, Wang D, Chen P, Stahl SS, Liu G. Science 353 1014-1018 (2016)
  2. Recent advances in micro reaction technology. Wiles C, Watts P. Chem Commun (Camb) 47 6512-6535 (2011)
  3. Irreversible Nek2 kinase inhibitors with cellular activity. Henise JC, Taunton J. J Med Chem 54 4133-4146 (2011)
  4. Importance of protein flexibility on molecular recognition: modeling binding mechanisms of aminopyrazine inhibitors to Nek2. Tang X, Wang Z, Lei T, Zhou W, Chang S, Li D. Phys Chem Chem Phys 20 5591-5605 (2018)
  5. Kinase inhibitor profile for human nek1, nek6, and nek7 and analysis of the structural basis for inhibitor specificity. Moraes EC, Meirelles GV, Honorato RV, de Souza Tde A, de Souza EE, Murakami MT, de Oliveira PS, Kobarg J. Molecules 20 1176-1191 (2015)
  6. Preclinical activity of MBM-5 in gastrointestinal cancer by inhibiting NEK2 kinase activity. Fang Y, Kong Y, Xi J, Zhu M, Zhu T, Jiang T, Hu W, Ma M, Zhang X. Oncotarget 7 79327-79341 (2016)
  7. Structure-guided design of purine-based probes for selective Nek2 inhibition. Coxon CR, Wong C, Bayliss R, Boxall K, Carr KH, Fry AM, Hardcastle IR, Matheson CJ, Newell DR, Sivaprakasam M, Thomas H, Turner D, Yeoh S, Wang LZ, Griffin RJ, Golding BT, Cano C. Oncotarget 8 19089-19124 (2017)
  8. In Silico Modeling of the Influence of Environment on Amyloid Folding Using FOD-M Model. Roterman I, Stapor K, Fabian P, Konieczny L. Int J Mol Sci 22 10587 (2021)
  9. Nek7 conformational flexibility and inhibitor binding probed through protein engineering of the R-spine. Byrne MJ, Nasir N, Basmadjian C, Bhatia C, Cunnison RF, Carr KH, Mas-Droux C, Yeoh S, Cano C, Bayliss R. Biochem J 477 1525-1539 (2020)
  10. Cross-coupling of mesylated phenol derivatives with potassium cyclopropyltrifluoroborate. Molander GA, Beaumard F, Niethamer TK. J Org Chem 76 8126-8130 (2011)
  11. 2-Arylamino-6-ethynylpurines are cysteine-targeting irreversible inhibitors of Nek2 kinase. Matheson CJ, Coxon CR, Bayliss R, Boxall K, Carbain B, Fry AM, Hardcastle IR, Harnor SJ, Mas-Droux C, Newell DR, Richards MW, Sivaprakasam M, Turner D, Griffin RJ, Golding BT, Cano C. RSC Med Chem 11 707-731 (2020)
  12. Discovery of potent NEK2 inhibitors as potential anticancer agents using structure-based exploration of NEK2 pharmacophoric space coupled with QSAR analyses. Khanfar MA, Khanfar MA, Banat F, Alabed S, Alqtaishat S. Mol Divers 21 187-200 (2017)
  13. Identification of pyrazine-based TrkA inhibitors: design, synthesis, evaluation, and computational modeling studies. Frett B, McConnell N, Wang Y, Xu Z, Ambrose A, Li HY. Medchemcomm 5 1507-1514 (2014)
  14. 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)
  15. A new tool for the chemical genetic investigation of the Plasmodium falciparum Pfnek-2 NIMA-related kinase. Mitcheson DF, Bottrill AR, Carr K, Coxon CR, Cano C, Golding BT, Griffin RJ, Fry AM, Doerig C, Bayliss R, Tobin AB. Malar J 15 535 (2016)
  16. Identification of a novel spirocyclic Nek2 inhibitor using high throughput virtual screening. Bhuiyan AI, Choi AH, Ghoshal S, Adiele UA, Dana D, Choi JY, Fath KR, Talele TT, Pathak SK. Bioorg Med Chem Lett 88 129288 (2023)
  17. Palladium-Catalyzed Synthesis of Cyclopropylthiophenes and Their Derivatization. Paškevičius T, Lapinskaitė R, Stončius S, Sadzevičienė R, Judžentienė A, Labanauskas L. Molecules 28 3770 (2023)


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