Molecular Diversity

, Volume 16, Issue 1, pp 27–51 | Cite as

The generation of purinome-targeted libraries as a means to diversify ATP-mimetic chemical classes for lead finding

  • Eduard R. Felder
  • Alessandra Badari
  • Teresa Disingrini
  • Sergio Mantegani
  • Christian Orrenius
  • Nilla Avanzi
  • Antonella Isacchi
  • Barbara Salom
Full-Length Paper


The generation of novel chemotypes in support of our oncology research projects expanded in recent years from a canonical design of kinase-targeted compound libraries to a broader interpretation of purinome-targeted libraries (PTL) addressing the specificity of cancer relevant targets such as kinases and ATPases. Successful screening of structurally diverse ATP-binding targets requires compound libraries covering multiple design elements, which may include phosphate surrogate moieties in ATPase inhibitors or far reaching lipophilic residues stabilizing inactive kinase conformations. Here, we exemplify the design and preparation of drug-like combinatorial libraries and report significantly enhanced screening performance on purinomic targets. We compared overall hit rates of PTL with a simultaneously tested unbiased collection of 200,000 compounds and found consistent superiority of the targeted libraries in all cases. We also analyzed the performance of the largest targeted libraries in comparison with each other and often found striking differences in how a specific target responds to various chemotypes and to whole collections.


Combinatorial chemistry Compound collection Drug design Kinase inhibitors Chemical space Fragment based Solid phase synthesis ATPase inhibitors Kinase selectivity 

Graphical Abstract


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Supplementary material

11030_2012_9361_MOESM1_ESM.pdf (1.6 mb)
ESM 1 (PDF 1,591 kb)


  1. 1.
    Manning G, White DB, Martinez RTH, Sudarsanam S (2002) The protein kinase complement of the human genome. Science 298: 1912–1934. doi: 10.1126/science.1075762 PubMedCrossRefGoogle Scholar
  2. 2.
    Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (1997) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 23: 3–25. doi: 10.1016/S0169-409X(96)00423-1 CrossRefGoogle Scholar
  3. 3.
    Leeson PD, Springthorpe B (2007) The influence of drug-like concepts on decision-making in medicinal chemistry. Nat Rev Drug Discov 6: 881–890. doi: 10.1038/nrd2445 PubMedCrossRefGoogle Scholar
  4. 4.
    Accelrys (2009) Pipeline Pilot. 8.0 edn., San Diego, CAGoogle Scholar
  5. 5.
    Lobell M, Hendrix M, Hinzen B, Keldenich J, Meier H, Schmeck C, Schohe-Loop R, Wunberg T, Hillisch A (2006) In silico ADMET traffic lights as a tool for the prioritization of HTS hits. ChemMedChem 1: 1229–1236. doi: 10.1002/cmdc.200600168 PubMedCrossRefGoogle Scholar
  6. 6.
    Lu JJ, Crimin K, Goodwin JT, Crivori P, Orrenius C, Xing L, Tandler PJ, Vidmar TJ, Amore BM, Wilson AGE, Stouten PFW, Burton PS (2004) Influence of molecular flexibility and polar surface area metrics on oral bioavailability in the rat. J Med Chem 47: 6104–6107. doi: 10.1021/jm0306529 PubMedCrossRefGoogle Scholar
  7. 7.
    Veber DF, Johnson SR, Cheng H-Y, Smith BR, Ward KW, Kopple KD (2002) Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem 45: 2615–2623. doi: 10.1021/jm020017n PubMedCrossRefGoogle Scholar
  8. 8.
    Tibco (2011) Spotfire. Somerville, MAGoogle Scholar
  9. 9.
    Malumbres M (2011) Physiological relevance of cell cycle kinases. Physiol Rev 91: 973–1007. doi: 10.1152/physrev.00025.2010 PubMedCrossRefGoogle Scholar
  10. 10.
    Zhang C, Kim S-H (2008) The Impact of protein kinase structures on drug discovery, Chapt 18. In: Stroud RM, Finer-Moore J (eds) Computational and structural approaches to drug discovery: ligand–protein interactions. The Royal Society of Chemistry, London, pp 349–365. doi: 10.1039/9781847557964 Google Scholar
  11. 11.
    Aronov AM, McClain B, Moody CS, Murcko MA (2008) Kinase-likeness and kinase-privileged fragments: toward virtual polypharmacology. J Med Chem 51: 1214–1222. doi: 10.1021/jm701021b PubMedCrossRefGoogle Scholar
  12. 12.
    Posy SL, Hermsmeier MA, Vaccaro W, Ott K-H, Todderud G, Lippy JS, Trainor GL, Loughney DA, Johnson SR (2011) Trends in kinase selectivity: insights for target class-focused library screening. J Med Chem 54: 54–66. doi: 10.1021/jm101195a PubMedCrossRefGoogle Scholar
  13. 13.
    Fancelli D, Moll J, Varasi M, Bravo R, Artico R, Berta D, Bindi S, Cameron A, Candiani I, Cappella P, Carpinelli P, Croci W, Forte B, Giorgini ML, Klapwijk J, Marsiglio A, Pesenti E, Rocchetti M, Roletto F, Severino D, Soncini C, Storici P, Tonani R, Zugnoni P, Vianello P (2006) 1,4,5,6-Tetrahydropyrrolo[3,4-c] pyrazoles: identification of a potent aurora kinase inhibitor with a favorable antitumor kinase inhibition profile. J Med Chem 49: 7247–7251PubMedCrossRefGoogle Scholar
  14. 14.
    Traquandi G, Ciomei M, Ballinari D, Casale E, Colombo N, Croci V, Fiorentini F, Isacchi A, Longo A, Mercurio C, Panzeri A, Pastori W, Pevarello P, Volpi D, Roussel P, Vulpetti A, Brasca MG (2010) Identification of potent pyrazolo[4,3-h]quinazoline-3-carboxamides as multi-cyclin-dependent kinase inhibitors. J Med Chem 53: 2171–2187. doi: 10.1021/jm901710h PubMedCrossRefGoogle Scholar
  15. 15.
    Menichincheri M (2009) First Cdc7 kinase inhibitors: pyrrolopyridinones as potent and orally active antitumor agents. 2. Lead discovery. J Med Chem 52: 293–307. doi: 10.1021/jm800977q PubMedCrossRefGoogle Scholar
  16. 16.
    Beria I, Bossi RT, Brasca MG, Caruso M, Ceccarelli W, Fachin G, Fasolini M, Forte B, Fiorentini F, Pesenti E, Pezzetta D, Posteri H, Scolaro A, Depaolini SR, Valsasina B (2011) NMS-P937, a 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivative as potent and selective Polo-like kinase 1 inhibitor. Bioorg Med Chem Lett 21: 2969–2974. doi: 10.1016/j.bmcl.2011.03.054 PubMedCrossRefGoogle Scholar
  17. 17.
    Bossi RT, Saccardo MB, Ardini E, Menichincheri M, Rusconi L, Magnaghi P, Orsini P, Avanzi N, Borgia AL, Nesi M, Bandiera T, Fogliatto G, Bertrand JA (2010) Crystal structures of anaplastic lymphoma kinase in complex with ATP competitive inhibitors. Biochemistry 49: 6813–6825. doi: 10.1021/bi1005514 PubMedCrossRefGoogle Scholar
  18. 18.
    Colombo R, Caldarelli M, Mennecozzi M, Giorgini ML, Sola F, Cappella P, Perrera C, Re Depaolini S, Rusconi L, Cucchi U, Avanzi N, Bertrand JA, Bossi RT, Pesenti E, Galvani A, Isacchi A, Colotta F, Donati D, Moll JK (2010) Targeting the mitotic checkpoint for cancer therapy with NMS-P715, an inhibitor of MPS1 kinase. Cancer Res 70: 10255–10264. doi: 10.1158/0008-5472.CAN-10-2101 PubMedCrossRefGoogle Scholar
  19. 19.
    Schindler T, Bornmann W, Pellicena P, Miller WT, Clarkson B, Kuriyan J (2000) Structural mechanism for STI-571 inhibition of Abelson tyrosine kinase. Science 289: 1938–1942. doi: 10.1126/science.289.5486.1938 PubMedCrossRefGoogle Scholar
  20. 20.
    Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP (2011) Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol 29: 1046–1051. doi: 10.1038/nbt.1990 PubMedCrossRefGoogle Scholar
  21. 21.
    Modugno M, Casale E, Soncini C, Rosettani P, Colombo R, Lupi R, Rusconi L, Fancelli D, Carpinelli P, Cameron AD, Isacchi A, Moll Jr (2007) Crystal structure of the T315I Abl mutant in complex with the aurora kinases inhibitor PHA-739358. Cancer Res 67: 7987–7990PubMedCrossRefGoogle Scholar
  22. 22.
    Chene P (2008) Challenges in design of biochemical assays for the identification of small molecules to target multiple conformations of protein kinases. Drug Discov Today 13: 522–529. doi: 10.1016/j.drudis.2008.03.023 PubMedCrossRefGoogle Scholar
  23. 23.
    Zuccotto F, Ardini E, Casale E, Angiolini M (2010) Through the “gatekeeper door”: exploiting the active kinase conformation. J Med Chem 53: 2681–2694. doi: 10.1021/jm901443h PubMedCrossRefGoogle Scholar
  24. 24.
    Chene P (2002) ATPases as drug targets: learning from their structure. Nat Rev Drug Discov 1: 665–673. doi: 10.1038/nrd894 PubMedCrossRefGoogle Scholar
  25. 25.
    Roe SM, Prodromou C, O’Brien R, Ladbury JE, Piper PW, Pearl LH (1999) Structural basis for inhibition of the Hsp90 molecular chaperone by the antitumor antibiotics radicicol and geldanamycin. J Med Chem 42: 260–266. doi: 10.1021/jm980403y PubMedCrossRefGoogle Scholar
  26. 26.
    Dalvit C, Ardini E, Fogliatto GP, Mongelli N, Veronesi M (2004) Reliable high-throughput functional screening with 3-FABS. Drug Discov Today 9: 595–602. doi: 10.1016/S1359-6446(04)03161-7 PubMedCrossRefGoogle Scholar
  27. 27.
    Dalvit C, Caronni D, Mongelli N, Veronesi M, Vulpetti A (2006) NMR-based quality control approach for the identification of false positives and false negatives in high throughput screening. Curr Drug Discov Technol 3: 115–124. doi: 10.2174/157016306778108875 PubMedCrossRefGoogle Scholar
  28. 28.
    Massey A, Williamson D, Browne H, Murray J, Dokurno P, Shaw T, Macias A, Daniels Z, Geoffroy S, Dopson M, Lavan P, Matassova N, Francis G, Graham C, Parsons R, Wang Y, Padfield A, Comer M, Drysdale M, Wood M (2010) A novel, small molecule inhibitor of Hsc70/Hsp70 potentiates Hsp90 inhibitor induced apoptosis in HCT116 colon carcinoma cells. Cancer Chemother Pharmacol 66: 535–545. doi: 10.1007/s00280-009-1194-3 PubMedCrossRefGoogle Scholar
  29. 29.
    De Kloe GE, Bailey D, Leurs R, de Esch IJP (2009) Transforming fragments into candidates: small becomes big in medicinal chemistry. Drug Discov Today 14: 630–646. doi: 10.1016/j.drudis.2009.03.009 PubMedCrossRefGoogle Scholar
  30. 30.
    Jankowska J, Sobkowski M, StawiÅski J, Kraszewski A (1994) Studies on aryl H-phosphonates. I. An efficient method for the preparation of deoxyribo- and ribonucleoside 3′-H-phosphonate monoesters by transesterification of diphenyl H-phosphonate. Tetrahedron Lett 35: 3355–3358. doi: 10.1016/S0040-4039(00)76906-1 CrossRefGoogle Scholar
  31. 31.
    Zegzouti H, Zdanovskaia M, Hsiao K, Goueli SA (2009) ADP-Glo: a bioluminescent and homogeneous ADP monitoring assay for kinases. Assay Drug Dev Technol 7: 560–572. doi: 10.1089/adt.2009.0222 PubMedCrossRefGoogle Scholar
  32. 32.
    Karaman MW, Herrgard S, Treiber DK, Gallant P, Atteridge CE, Campbell BT, Chan KW, Ciceri P, Davis MI, Edeen PT, Faraoni R, Floyd M, Hunt JP, Lockhart DJ, Milanov ZV, Morrison MJ, Pallares G, Patel HK, Pritchard S, Wodicka LM, Zarrinkar PP (2008) A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol 26: 127–132. doi: 10.1038/nbt1358 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2012

Authors and Affiliations

  • Eduard R. Felder
    • 1
  • Alessandra Badari
    • 1
  • Teresa Disingrini
    • 1
  • Sergio Mantegani
    • 1
  • Christian Orrenius
    • 1
  • Nilla Avanzi
    • 1
  • Antonella Isacchi
    • 1
  • Barbara Salom
    • 1
  1. 1.Oncology ResearchNerviano Medical SciencesNervianoItaly

Personalised recommendations