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KINASE LIBRARIES

 

 

Epidermal Growth Factor Receptor tyrosine kinase domain with 4-anilinoquinazoline inhibitor erlotinib

(1 conformation / schematic representation)

Kinases are critical proteins playing a role in the cascade transmission of cell signals transferring phosphate groups from ATP or ATP-like molecules to substrates (phosphorylation process). They are directly involved in numerous diseases, particularly cancer and inflammation, and became one of the most studied families of receptors for the development of new drugs. More than 500 kinases were identified in humans and could be suitable targets.

Commercialisation of imatinib (Gleevec) for the treatment of chronic leukemia, of gefitinib (Iressa) and erlotinib (Tarceva) for the treatment of lung cancer showed that small molecules inhibiting protein kinases could be efficient drugs. More than 40 kinase inhibitors are currently analysed in pre-clinical studies. Most of those molecules target the ATP site of the kinase but researchers also try to inhibit the non-ATP site to obtain selectivity.

For a better understanding of the mechanisms of those proteins, new approaches and structures are needed to identify ligands. Kinases were clustered with respect to the homology of their structure. The existence of privileged scaffolds was demonstrated for some families. Parallel synthesis allows to rapidly assess the potential of new chemical series. Molecular models are also useful when trying to select the appropriate combinations (eg : Gozalbes, R. ; Simon, L. ; Froloff, N. ; Sartori, E. ; Monteils, C. ; Baudelle, R. “Development and Experimental Validation of a Docking Strategy for the Generation of Kinase-Targeted Librairies” J. Med. Chem., 2008, 51, 3124-3132.)

AMINOPYRIDINE & AMINOPYRIMIDINE LIBRARY
AMINOPYRIDINE & AMINOPYRIMIDINE LIBRARY

• highly diverse exploration of aminopyridines, aminopyrimidines and purine-like structures
• privileged structure for kinase inhibitors
• scaffolds related to interesting leads for the exploration of the "kinome" and to natural derivatives with complex pharmacology
• sophisticated production process increasing structural diversity
• library based on 48 intermediates

AZAINDOLE LIBRARY
AZAINDOLE LIBRARY

• highly diverse exploration of original azaindole scaffold
• privileged structures for kinase and enzyme inhibitors
• scaffolds also present in GPCR inhibitors
• many example of better pharmacokinetics than indoles
• library based on 10 intermediates

CHEMHIT3
CHEMHIT3

• diverse exploration of original small aza-heterocycles
• privileged structures for kinase inhibitions
• isosteric applications for indole analogs
• strictly respect of Lipinski’s rules
• library based on 10 intermediates

DIAMINOPYRIMIDINE LIBRARY
DIAMINOPYRIMIDINE LIBRARY

• privileged structure for exploring the human kinome
• core structures chosen to enhance kinase hit rate
• experimental validation
• druggable structures with good Lipinski characteristics
• library based on 27 intermediates

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