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4-(Pyrazol-4-yl)-pyrimidines as selective inhibitors of cyclin-dependent kinase 4/6.

Cho YS, Borland M, Brain C, Chen CH, Cheng H, Chopra R, Chung K, Groarke J, He G, Hou Y, Kim S, Kovats S, Lu Y, O'Reilly M, Shen J, Smith T, Trakshel G, Vögtle M, Xu M, Xu M, Sung MJ
J Med Chem 53 7938-57 (2010)
Cited: 26 times
EuropePMC logo PMID: 21038853

Abstract

Identification and structure-guided optimization of a series of 4-(pyrazol-4-yl)-pyrimidines as selective CDK4/6 inhibitors is reported herein. Several potency and selectivity determinants were established based on the X-ray crystallographic analysis of representative compounds bound to monomeric CDK6. Significant selectivity for CDK4/6 over CDK1 and CDK2 was demonstrated with several compounds in both enzymatic and cellular assays.

Reviews - 3nux mentioned but not cited (3)

  1. The underappreciated role of allostery in the cellular network. Nussinov R, Tsai CJ, Ma B. Annu Rev Biophys 42 169-189 (2013)
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  1. A strategy based on protein-protein interface motifs may help in identifying drug off-targets. Engin HB, Keskin O, Nussinov R, Gursoy A. J Chem Inf Model 52 2273-2286 (2012)
  2. Identification of gefitinib off-targets using a structure-based systems biology approach; their validation with reverse docking and retrospective data mining. Verma N, Rai AK, Kaushik V, Brünnert D, Chahar KR, Pandey J, Goyal P. Sci Rep 6 33949 (2016)
  3. Chemical space exploration based on recurrent neural networks: applications in discovering kinase inhibitors. Li X, Xu Y, Yao H, Lin K. J Cheminform 12 42 (2020)
  4. Identification of abemaciclib derivatives targeting cyclin-dependent kinase 4 and 6 using molecular dynamics, binding free energy calculation, synthesis, and pharmacological evaluation. Zhou Y, Li X, Luo P, Chen H, Zhou Y, Zheng X, Yin Y, Wei H, Liu H, Xia W, Shi M, Li X. Front Pharmacol 14 1154654 (2023)


Reviews citing this publication (4)

  1. Recent Progress in CDK4/6 Inhibitors and PROTACs. Wang H, Ba J, Kang Y, Gong Z, Liang T, Zhang Y, Qi J, Wang J. Molecules 28 8060 (2023)
  2. Selective inhibition of CDK4/6: A safe and effective strategy for developing anticancer drugs. Yuan K, Wang X, Dong H, Min W, Hao H, Yang P. Acta Pharm Sin B 11 30-54 (2021)
  3. Targeting CDK4/6 for Anticancer Therapy. Qi J, Ouyang Z. Biomedicines 10 685 (2022)
  4. Therapeutic potential of CDK4/6 inhibitors in renal cell carcinoma. Sager RA, Backe SJ, Ahanin E, Smith G, Nsouli I, Woodford MR, Bratslavsky G, Bourboulia D, Mollapour M. Nat Rev Urol 19 305-320 (2022)

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  1. Inhibiting CDK6 Activity by Quercetin Is an Attractive Strategy for Cancer Therapy. Yousuf M, Khan P, Shamsi A, Shahbaaz M, Hasan GM, Haque QMR, Christoffels A, Islam A, Hassan MI. ACS Omega 5 27480-27491 (2020)
  2. Fragment-Based Discovery of 7-Azabenzimidazoles as Potent, Highly Selective, and Orally Active CDK4/6 Inhibitors. Cho YS, Angove H, Brain C, Chen CH, Cheng H, Cheng R, Chopra R, Chung K, Congreve M, Dagostin C, Davis DJ, Feltell R, Giraldes J, Hiscock SD, Kim S, Kovats S, Lagu B, Lewry K, Loo A, Lu Y, Luzzio M, Maniara W, McMenamin R, Mortenson PN, Benning R, O'Reilly M, Rees DC, Shen J, Smith T, Wang Y, Williams G, Woolford AJ, Wrona W, Xu M, Yang F, Howard S. ACS Med Chem Lett 3 445-449 (2012)
  3. Facile syntheses of novel benzo-1,3-dioxolo-, benzothiazolo-, pyrido-, and quinolino-fused 5H-benzo[d]-pyrazolo[5,1-b][1,3]-oxazines and 1H-pyrazoles. Avila B, Solano DM, Haddadin MJ, Kurth MJ. Org. Lett. 13 1060-1063 (2011)
  4. Methods for Discovering and Targeting Druggable Protein-Protein Interfaces and Their Application to Repurposing. Ozdemir ES, Halakou F, Nussinov R, Gursoy A, Keskin O. Methods Mol Biol 1903 1-21 (2019)
  5. Discovery of 4,6-disubstituted pyrimidines as potent inhibitors of the heat shock factor 1 (HSF1) stress pathway and CDK9. Rye CS, Chessum NE, Lamont S, Pike KG, Faulder P, Demeritt J, Kemmitt P, Tucker J, Zani L, Cheeseman MD, Isaac R, Goodwin L, Boros J, Raynaud F, Hayes A, Henley AT, de Billy E, Lynch CJ, Sharp SY, Te Poele R, Fee LO, Foote KM, Green S, Workman P, Jones K. Medchemcomm 7 1580-1586 (2016)
  6. Development of a time-resolved fluorescence resonance energy transfer assay for cyclin-dependent kinase 4 and identification of its ATP-noncompetitive inhibitors. Lo MC, Ngo R, Dai K, Li C, Liang L, Lee J, Emkey R, Eksterowicz J, Ventura M, Young SW, Xiao SH. Anal. Biochem. 421 368-377 (2012)
  7. Palbociclib can overcome mutations in cyclin dependent kinase 6 that break hydrogen bonds between the drug and the protein. Hernandez Maganhi S, Jensen P, Caracelli I, Zukerman Schpector J, Fröhling S, Friedman R. Protein Sci. 26 870-879 (2017)
  8. Drug targets for cell cycle dysregulators in leukemogenesis: in silico docking studies. Jayaraman A, Jamil K. PLoS ONE 9 e86310 (2014)
  9. Ellagic Acid Controls Cell Proliferation and Induces Apoptosis in Breast Cancer Cells via Inhibition of Cyclin-Dependent Kinase 6. Yousuf M, Shamsi A, Khan P, Shahbaaz M, AlAjmi MF, Hussain A, Hassan GM, Islam A, Rizwanul Haque QM, Hassan MI. Int J Mol Sci 21 (2020)
  10. Synthesis of a 2,4,6-trisubstituted 5-cyano-pyrimidine library and evaluation of its immunosuppressive activity in a Mixed Lymphocyte Reaction assay. Stella A, Van Belle K, De Jonghe S, Louat T, Herman J, Rozenski J, Waer M, Herdewijn P. Bioorg. Med. Chem. 21 1209-1218 (2013)
  11. 2-Methylpyridine-1-ium-1-sulfonate as an Inducer of Apoptosis and Cell Cycle Arrest: A comparative in vitro and Computational Study. Mohammadi-Motlagh HR, Yarani R, Sadeghalvad M, Adham E, Rasouli H, Mostafaie A. Nutr Cancer 71 643-656 (2019)
  12. A Search for Cyclin-Dependent Kinase 4/6 Inhibitors by Pharmacophore-Based Virtual Screening, Molecular Docking, and Molecular Dynamic Simulations. Susanti NMP, Damayanti S, Kartasasmita RE, Tjahjono DH. Int J Mol Sci 22 13423 (2021)
  13. Discovery of N,4-Di(1H-pyrazol-4-yl)pyrimidin-2-amine-Derived CDK2 Inhibitors as Potential Anticancer Agents: Design, Synthesis, and Evaluation. Fanta BS, Lenjisa J, Teo T, Kou L, Mekonnen L, Yang Y, Basnet SKC, Hassankhani R, Sykes MJ, Yu M, Wang S. Molecules 28 2951 (2023)
  14. Discovery of new small-molecule cyclin-dependent kinase 6 inhibitors through computational approaches. Luo X, Zhao Y, Tang P, Du X, Li F, Wang Q, Li R, He J. Mol Divers 25 367-382 (2021)
  15. Synthesis and In Silico Docking of New Pyrazolo[4,3-e]pyrido[1,2-a]pyrimidine-based Cytotoxic Agents. Horchani M, Heise NV, Hoenke S, Csuk R, Harrath AH, Ben Jannet H, Romdhane A. Int J Mol Sci 22 10258 (2021)


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