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Structure-based design of 2-arylamino-4-cyclohexylmethyl-5-nitroso-6-aminopyrimidine inhibitors of cyclin-dependent kinases 1 and 2.

Sayle KL, Bentley J, Boyle FT, Calvert AH, Cheng Y, Curtin NJ, Endicott JA, Golding BT, Hardcastle IR, Jewsbury P, Mesguiche V, Newell DR, Noble ME, Parsons RJ, Pratt DJ, Wang LZ, Griffin RJ
Bioorg Med Chem Lett 13 3079-82 (2003)
Cited: 27 times
EuropePMC logo PMID: 12941338

Abstract

A series of O(4)-cyclohexylmethyl-5-nitroso-6-aminopyrimidines bearing 2-arylamino substituents was synthesised and evaluated for CDK1 and CDK2 inhibitory activity. Consistent with analogous studies with O(6)-cyclohexylmethylpurines, 2-arylaminopyrimidines with a sulfonamide or carboxamide group at the 4'-position were potent inhibitors, with IC(50) values against CDK2 of 1.1+/-0.3 and 34+/-8 nM, respectively. The crystal structure of the 4'-carboxamide derivative, in complex with phospho-Thr160 CDK2/cyclin A, confirmed the expected binding mode of the inhibitor, and revealed an additional interaction between the carboxamide function and an aspartate residue.

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  2. Rapid Identification of Inhibitors and Prediction of Ligand Selectivity for Multiple Proteins: Application to Protein Kinases. Ma Z, Huang SY, Cheng F, Zou X. J Phys Chem B 125 2288-2298 (2021)


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  2. IRAK-4 inhibitors for inflammation. Wang Z, Wesche H, Stevens T, Walker N, Yeh WC. Curr Top Med Chem 9 724-737 (2009)
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  1. Novel small molecule inhibitors of 3-phosphoinositide-dependent kinase-1. Feldman RI, Wu JM, Polokoff MA, Kochanny MJ, Dinter H, Zhu D, Biroc SL, Alicke B, Bryant J, Yuan S, Buckman BO, Lentz D, Ferrer M, Whitlow M, Adler M, Finster S, Chang Z, Arnaiz DO. J Biol Chem 280 19867-19874 (2005)
  2. Combined PI3K and CDK2 inhibition induces cell death and enhances in vivo antitumour activity in colorectal cancer. Beale G, Haagensen EJ, Thomas HD, Wang LZ, Revill CH, Payne SL, Golding BT, Hardcastle IR, Newell DR, Griffin RJ, Cano C. Br J Cancer 115 682-690 (2016)
  3. 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)
  4. Effect of electrostatic polarization and bridging water on CDK2-ligand binding affinities calculated using a highly efficient interaction entropy method. Duan L, Feng G, Feng G, Wang X, Wang L, Zhang Q. Phys Chem Chem Phys 19 10140-10152 (2017)
  5. IRAK-4 inhibitors. Part II: a structure-based assessment of imidazo[1,2-a]pyridine binding. Buckley GM, Ceska TA, Fraser JL, Gowers L, Groom CR, Higueruelo AP, Jenkins K, Mack SR, Morgan T, Parry DM, Pitt WR, Rausch O, Richard MD, Sabin V. Bioorg Med Chem Lett 18 3291-3295 (2008)
  6. 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)
  7. The effect of a tightly bound water molecule on scaffold diversity in the computer-aided de novo ligand design of CDK2 inhibitors. García-Sosa AT, Mancera RL. J Mol Model 12 422-431 (2006)
  8. Synthesis of N-tetra-O-acetyl-beta-D-glucopyranosyl-N'-(4',6'-diarylpyrimidin-2'-yl)thioureas. Thanh ND, Mai NT. Carbohydr Res 344 2399-2405 (2009)
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  11. Synthesis, in vitro antibacterial and antifungal evaluations of 2-amino-4-(1-naphthyl)-6-arylpyrimidines. Ingarsal N, Saravanan G, Amutha P, Nagarajan S. Eur J Med Chem 42 517-520 (2007)
  12. Facilitation of addition-elimination reactions in pyrimidines and purines using trifluoroacetic acid in trifluoroethanol. Whitfield HJ, Griffin RJ, Hardcastle IR, Henderson A, Meneyrol J, Mesguiche V, Sayle KL, Golding BT. Chem Commun (Camb) 2802-2803 (2003)
  13. Molecular modelling on small molecular CDK2 inhibitors: an integrated approach using a combination of molecular docking, 3D-QSAR and pharmacophore modelling. Yuan H, Liu H, Tai W, Wang F, Zhang Y, Yao S, Ran T, Lu S, Ke Z, Xiong X, Xu J, Chen Y, Lu T. SAR QSAR Environ Res 24 795-817 (2013)
  14. Structure-based design of 2-arylamino-4-cyclohexylmethoxy-5-nitroso-6-aminopyrimidine inhibitors of cyclin-dependent kinase 2. Marchetti F, Sayle KL, Bentley J, Clegg W, Curtin NJ, Endicott JA, Golding BT, Griffin RJ, Haggerty K, Harrington RW, Mesguiche V, Newell DR, Noble ME, Parsons RJ, Pratt DJ, Wang LZ, Hardcastle IR. Org Biomol Chem 5 1577-1585 (2007)
  15. Design, synthesis, spectral analysis and in vitro microbiological evaluation of 2-phenyl-3-(4,6-diarylpyrimidin-2-yl)thiazolidin-4-ones. Gopalakrishnan M, Thanusu J, Kanagarajan V. J Enzyme Inhib Med Chem 24 1088-1094 (2009)
  16. Molecular docking, synthesis and biological significance of pyrimidine analogues as prospective antimicrobial and antiproliferative agents. Kumar S, Kaushik A, Narasimhan B, Shah SAA, Lim SM, Ramasamy K, Mani V. BMC Chem 13 85 (2019)
  17. An eco-friendly and water mediated product selective synthesis of 2-aminopyrimidines and their in vitro anti-bacterial evaluation. Nagarajan S, Shanmugavelan P, Sathishkumar M, Selvi R, Ponnuswamy A, Harikrishnan H, Shanmugaiah V, Murugavel S. Bioorg Med Chem Lett 24 4999-5007 (2014)
  18. Exponential repulsion improves structural predictability of molecular docking. Bazgier V, Berka K, Otyepka M, Banáš P. J Comput Chem 37 2485-2494 (2016)
  19. 4-(4-morpholinophenyl)-6-arylpyrimidin-2-amines: synthesis, spectral analysis, and in vitro microbiological evaluation. Thanusu J, Kanagarajan V, Gopalakrishnan M. J Enzyme Inhib Med Chem 25 347-353 (2010)
  20. Discovery of Potential Inhibitors of CDK1 by Integrating Pharmacophore-Based Virtual Screening, Molecular Docking, Molecular Dynamics Simulation Studies, and Evaluation of Their Inhibitory Activity. Teotia V, Jha P, Chopra M. ACS Omega 9 39873-39892 (2024)
  21. Scaffold Hopping Approach to a New Series of Pyridine Derivatives as Potent Inhibitors of CDK2. Xu X, Yao Q. Arch Pharm (Weinheim) 349 224-231 (2016)


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