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Development of highly potent and selective diaminothiazole inhibitors of cyclin-dependent kinases.

Schonbrunn E, Betzi S, Alam R, Martin MP, Becker A, Han H, Francis R, Chakrasali R, Jakkaraj S, Kazi A, Sebti SM, Cubitt CL, Gebhard AW, Hazlehurst LA, Tash JS, Georg GI
J Med Chem 56 3768-82 (2013)

Cited: 30 times
EuropePMC logo PMID: 23600925

Abstract

Cyclin-dependent kinases (CDKs) are serine/threonine protein kinases that act as key regulatory elements in cell cycle progression. We describe the development of highly potent diaminothiazole inhibitors of CDK2 (IC50 = 0.0009-0.0015 μM) from a single hit compound with weak inhibitory activity (IC50 = 15 μM), discovered by high-throughput screening. Structure-based design was performed using 35 cocrystal structures of CDK2 liganded with distinct analogues of the parent compound. The profiling of compound 51 against a panel of 339 kinases revealed high selectivity for CDKs, with preference for CDK2 and CDK5 over CDK9, CDK1, CDK4, and CDK6. Compound 51 inhibited the proliferation of 13 out of 15 cancer cell lines with IC50 values between 0.27 and 6.9 μM, which correlated with the complete suppression of retinoblastoma phosphorylation and the onset of apoptosis. Combined, the results demonstrate the potential of this new inhibitors series for further development into CDK-specific chemical probes or therapeutics.

Articles - 3rmf mentioned but not cited (1)

  1. Development of highly potent and selective diaminothiazole inhibitors of cyclin-dependent kinases. Schonbrunn E, Betzi S, Alam R, Martin MP, Becker A, Han H, Francis R, Chakrasali R, Jakkaraj S, Kazi A, Sebti SM, Cubitt CL, Gebhard AW, Hazlehurst LA, Tash JS, Georg GI. J Med Chem 56 3768-3782 (2013)


Reviews citing this publication (5)

  1. Mitigating risk in academic preclinical drug discovery. Dahlin JL, Inglese J, Walters MA. Nat Rev Drug Discov 14 279-294 (2015)
  2. The essential roles of chemistry in high-throughput screening triage. Dahlin JL, Walters MA. Future Med Chem 6 1265-1290 (2014)
  3. Development and therapeutic potential of 2-aminothiazole derivatives in anticancer drug discovery. Alizadeh SR, Hashemi SM. Med Chem Res 30 771-806 (2021)
  4. Review of rationale and progress toward targeting cyclin-dependent kinase 2 (CDK2) for male contraception†. Faber EB, Wang N, Georg GI. Biol Reprod 103 357-367 (2020)
  5. Multitargeting the Action of 5-HT6 Serotonin Receptor Ligands by Additional Modulation of Kinases in the Search for a New Therapy for Alzheimer's Disease: Can It Work from a Molecular Point of View? Czarnota-Łydka K, Kucwaj-Brysz K, Pyka P, Haberek W, Podlewska S, Handzlik J. Int J Mol Sci 23 8768 (2022)

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  2. 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)
  3. Discovery of Diverse Small-Molecule Inhibitors of Mammalian Sterile20-like Kinase 3 (MST3). Olesen SH, Zhu JY, Martin MP, Schönbrunn E. ChemMedChem 11 1137-1144 (2016)
  4. miR-98 and its host gene Huwe1 target Caspase-3 in Silica nanoparticles-treated male germ cells. Xu B, Mao Z, Ji X, Yao M, Chen M, Zhang X, Hang B, Liu Y, Tang W, Tang Q, Xia Y. Sci Rep 5 12938 (2015)
  5. Identification of novel CDK2 inhibitors by a multistage virtual screening method based on SVM, pharmacophore and docking model. Liang JW, Wang MY, Wang S, Li SL, Li WQ, Meng FH. J Enzyme Inhib Med Chem 35 235-244 (2020)
  6. A Novel Vasoactive Proline-Rich Oligopeptide from the Skin Secretion of the Frog Brachycephalus ephippium. Arcanjo DD, Vasconcelos AG, Comerma-Steffensen SG, Jesus JR, Silva LP, Pires Júnior OR, Costa-Neto CM, Oliveira EB, Migliolo L, Franco OL, Restini CB, Paulo M, Bendhack LM, Bemquerer MP, Oliveira AP, Simonsen U, Leite JR. PLoS One 10 e0145071 (2015)
  7. Computational Simulations Identify Pyrrolidine-2,3-Dione Derivatives as Novel Inhibitors of Cdk5/p25 Complex to Attenuate Alzheimer's Pathology. Zeb A, Kim D, Alam SI, Son M, Kumar R, Rampogu S, Parameswaran S, Shelake RM, Rana RM, Parate S, Kim JY, Lee KW. J Clin Med 8 E746 (2019)
  8. Binding selectivity-dependent molecular mechanism of inhibitors towards CDK2 and CDK6 investigated by multiple short molecular dynamics and free energy landscapes. Wang L, Lu D, Wang Y, Xu X, Zhong P, Yang Z. J Enzyme Inhib Med Chem 38 84-99 (2023)
  9. In silico design and biological evaluation of a dual specificity kinase inhibitor targeting cell cycle progression and angiogenesis. Latham AM, Kankanala J, Fearnley GW, Gage MC, Kearney MT, Homer-Vanniasinkam S, Wheatcroft SB, Fishwick CW, Ponnambalam S. PLoS One 9 e110997 (2014)
  10. Repositioning of a Diaminothiazole Series Confirmed to Target the Cyclin-Dependent Kinase CRK12 for Use in the Treatment of African Animal Trypanosomiasis. Smith A, Wall RJ, Patterson S, Rowan T, Rico Vidal E, Stojanovski L, Huggett M, Hampton SE, Thomas MG, Corpas Lopez V, Gillingwater K, Duke J, Napier G, Peter R, Vitouley HS, Harrison JR, Milne R, Jeacock L, Baker N, Davis SH, Simeons F, Riley J, Horn D, Brun R, Zuccotto F, Witty MJ, Wyllie S, Read KD, Gilbert IH. J Med Chem 65 5606-5624 (2022)
  11. Role of microRNA-4458 in patients with non-small-cell lung cancer. Bao L, Wang L, Wei G, Wang Y, Wuyun G, Bo A. Oncol Lett 12 3958-3966 (2016)
  12. visGReMLIN: graph mining-based detection and visualization of conserved motifs at 3D protein-ligand interface at the atomic level. Ribeiro VS, Santana CA, Fassio AV, Cerqueira FR, da Silveira CH, Romanelli JPR, Patarroyo-Vargas A, Oliveira MGA, Gonçalves-Almeida V, Izidoro SC, de Melo-Minardi RC, Silveira SA, Silveira SA. BMC Bioinformatics 21 80 (2020)
  13. Discovery of nitroaryl urea derivatives with antiproliferative properties. Wróbel TM, Kiełbus M, Kaczor AA, Kryštof V, Karczmarzyk Z, Wysocki W, Fruziński A, Król SK, Grabarska A, Stepulak A, Matosiuk D. J Enzyme Inhib Med Chem 31 608-618 (2016)
  14. Structure of cyclin-dependent kinase 2 (CDK2) in complex with the specific and potent inhibitor CVT-313. Talapati SR, Nataraj V, Pothuganti M, Gore S, Ramachandra M, Antony T, More SS, Krishnamurthy NR. Acta Crystallogr F Struct Biol Commun 76 350-356 (2020)
  15. Tizoxanide Promotes Apoptosis in Glioblastoma by Inhibiting CDK1 Activity. Huang S, Xiao J, Wu J, Liu J, Feng X, Yang C, Xiang D, Luo S. Front Pharmacol 13 895573 (2022)
  16. Oxazinethione Derivatives as a Precursor to Pyrazolone and Pyrimidine Derivatives: Synthesis, Biological Activities, Molecular Modeling, ADME, and Molecular Dynamics Studies. Abdellattif MH, Shahbaaz M, Arief MMH, Hussien MA. Molecules 26 5482 (2021)
  17. Synthesis, cytotoxicity evaluation and molecular docking studies on 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone derivatives. Khamto N, Chaichuang L, Rithchumpon P, Phupong W, Bhoopong P, Tateing S, Pompimon W, Semakul N, Chomsri NO, Meepowpan P. RSC Adv 11 31433-31447 (2021)
  18. Tetrahydroindazole inhibitors of CDK2/cyclin complexes. Lee JC, Hong KH, Becker A, Tash JS, Schönbrunn E, Georg GI. Eur J Med Chem 214 113232 (2021)
  19. Collaborative Approach between Explainable Artificial Intelligence and Simplified Chemical Interactions to Explore Active Ligands for Cyclin-Dependent Kinase 2. Shimazaki T, Tachikawa M. ACS Omega 7 10372-10381 (2022)
  20. Creation of targeted compound libraries based on 3D shape recognition. Kyrylchuk A, Kravets I, Cherednichenko A, Tararina V, Kapeliukha A, Dudenko D, Protopopov M. Mol Divers 27 939-949 (2023)
  21. Development of a 2,4-Diaminothiazole Series for the Treatment of Human African Trypanosomiasis Highlights the Importance of Static-Cidal Screening of Analogues. Cleghorn LAT, Wall RJ, Albrecht S, MacGowan SA, Norval S, De Rycker M, Woodland A, Spinks D, Thompson S, Patterson S, Corpas Lopez V, Dey G, Collie IT, Hallyburton I, Kime R, Simeons FRC, Stojanovski L, Frearson JA, Wyatt PG, Read KD, Gilbert IH, Wyllie S. J Med Chem 66 8896-8916 (2023)
  22. Development of allosteric and selective CDK2 inhibitors for contraception with negative cooperativity to cyclin binding. Faber EB, Sun L, Tang J, Roberts E, Ganeshkumar S, Wang N, Rasmussen D, Majumdar A, Hirsch LE, John K, Yang A, Khalid H, Hawkinson JE, Levinson NM, Chennathukuzhi V, Harki DA, Schönbrunn E, Georg GI. Nat Commun 14 3213 (2023)
  23. Emerging approaches to CDK inhibitor development, a structural perspective. Hope I, Endicott JA, Watt JE. RSC Chem Biol 4 146-164 (2023)
  24. GC/MS Analysis, Cytotoxicity, and Antiviral Activities of Annona glabra Hexane Extract Supported by In Silico Study. Soleman DM, Eldahshan OA, Ibrahim MH, Ogaly HA, Galal HM, Batiha GE, Elkousy RH. Molecules 28 1628 (2023)


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