Bringing Kinases Into Focus

 

Veronique Birault, John Harris, Joelle Le, Mike Lipkin, Ravi Nerella and Adrian Stevens

 

BioFocus Discovery Ltd., Chesterford Research Park, Saffron Walden, Essex, UK.

 

The sequencing of the human genome[1], [2] has led to the identification of approximately 20,000-25,000 genes in human DNA[3].  This groundbreaking achievement has meant that it is now possible to putatively identify all proteins in a target class (cf. protein family).  For example, ca. 518 protein kinases[4] and at least 350 GPCRs that can be considered to be ‘drug-able’[5], [6] have been identified.  With the emergence of literally thousands of new protein targets with the potential for therapeutic drug intervention, a need has emerged for design strategies to be relevant to the genomic scale.  For example, how can novel protein family members, which might lack both structural and small molecule data, be explored?

 

In response to these drug design challenges, a new field of informatics has emerged[7].  Chemogenomics can be considered as an approach that structures the drug discovery process in parallel to gene (or, more correctly, protein) families rather than single gene/protein targets.  By adopting an approach that parallels entire protein gene families, chemogenomics attempts to make synergistic use of all information across that family.  In particular, it exploits the concept that structure-activity relationships (SAR) for known members of a family might be useful in aiding the drug design process for either poorly understood or previously unknown members of the same family.

 

In recent years, a number of chemogenomics-based drug design approaches have been reported in the literature (for example see references [8], [9], [10], [11], [12], [13]).  Whilst they are based on variety of different analytical methodologies, these approaches all endeavour to derive relationships between gene-derived protein sequence and small molecule SAR.  In the present paper, we illustrate the development and subsequent utility of such a chemogenomic approach on the therapeutically important gene class of protein kinases[14], [15].


 

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[2].     Venter J.C., Adams M.D., Myers E.W., Li P.W., Mural R.J., Sutton G.G., Smith H.O., Yandell M., Evans C.A., Holt R.A., et al. The Sequence of the Human Genome. Science, 2001, 291, 1304-1351.

[3].     She X., Jiang Z., Clark R.A., Liu G., Cheng Z., Tuzun E., Church D.M., Sutton G., Halpern A.L. & Eichler E.E. Shotgun Sequence Assembly and Recent Segmental Duplications Within the Human Genome. Nature, 2004, 431, 927-930.

[4].     Manning G., Whyte D.B., Martinez R., Hunter T., Sudarsanam, S. The Protein Kinase Complement of the Human Genome. Science, 2002, 298, 1912.

[5].     Hopkins A.L., Groom C.R. The Druggable Genome, Nature Reviews Drug Discovery, 2002, 1, 727 –730.

[6].     For example, see Wise A., Gearing K., Rees S. Target Validation of G-Protein Coupled Receptors. DDT, 2002, 7(4), 235-246.

[7].     Caron P.R., Mullican M.D., Mashal R.D., Wilson K.P., Su M.S., Murcko M.A. Chemogenomic approaches to drug discovery. Curr. Opinion Chem. Biol., 2001, 5(4), 464-470.

[8].     Crossley R., Rose V.S., Stevens A.P. Construction of libraries of compounds focused towards receptors and other biological targets for screening and design of drugs or agrochemicals. PCT Int. Appl. WO 03/004147 A2, 2003.

[9].     ter Haar, E., Walters, W.P., Pazhanisamy, S., Taslimi P., Pierce, A.C., Bernis, G.W., Salituro, F.G., Harbeson, S.L. Kinase Chemogenomics: Targeting the Human Kinome for Target Validation and Drug Discovery. Mini-Rev. Med. Chem., 2004, 4, 235-253.

[10].   Deng, Z., Chuaqui, C., Singh J. Structural Interaction Fingerprint (SIFt): A Novel Method of Analysing Three-Dimensional Protein-Ligand Binding Interactions. J. Med. Chem., 2004, 47, 337-344.

[11].   Chuaqui, C., Deng, Z., Singh J. Interaction Profiles of Protein Kinases – Inhibitor Complexes and their Application in Virtual Screening. J. Med. Chem., 2005, 48, 121-133.

[12].   Vieth, M., Higgs, R.E., Robertson, D.H., Shapiro, M., Gragg, E.A., Hemmerle, H. Kinomics – Structural Biology and Chemogenomics of Kinase Inhibitors and Targets.  Biochim. Biophys. Acta, 2004, 243-257.

[13].   Schuffenhauer A., Jacoby E. Annotating and Mining the Ligand-Target Chemogenomics Knowledge Space.  Drug Discovery Today: BIOSILICO, 2004, 2(5), 190-200.

[14].   Cohen P. Protein kinases – the major drug targets of the twenty-first century? Nature Reviews 2002, 1, 309-15.

[15].   Waters N.C., Geyer J.A. Cyclin-dependent protein kinases as therapeutic drug targets for antimalarial drug development. Expert Opin. Ther. Targets, 2003, 7(1), 7-17.