Global Discovery Chemistry
Today’s drug discovery project portfolios are moving into uncharted target space. The discovery of tractable ligands followed by biological interrogation of the target will be critical for enabling future projects. Typically, such targets have large, shallow, or weakly defined areas for ligand interaction, which are not well suited for small molecule approaches. Macrocyclic peptides are considered an appropriate chemical format to address the ligandability of such difficult targets. However, traditional macrocyclic peptide approaches based on synthesizing relatively small cyclic peptide arrays for screening have been met with limited success thus far. Peptide display technologies based on natural amino acids opened up new opportunities to interrogate therapeutic targets. We have recently in-licensed a technology platform from PeptiDream based on a peptide mRNA display approach that permits incorporation of un-natural as well as natural amino acids into its display libraries, allowing far greater opportunity to generate hits against uncharted targets. We believe there are significant opportunities to further develop the platform by exploring novel amino acids and new cyclization schemes geared toward expanding biologically relevant chemical space. Concerning amino acid synthesis expertise and the design of new cyclization mechanism, we are collaborating with an internal multidisciplinary team and an established academic network.
Discovery of novel allosteric non-bisphosphonate inhibitors of farnesyl pyrophosphate synthase by integrated lead finding.
Marzinzik AL, Amstutz R, Bold G, Bourgier E, Cotesta S, Glickman JF, Goette M, Henry C, Lehmann S, Hartwieg JCD.
ChemMedChem. 2015; 10(11): 1884-1891.
A general strategy for targeting drugs to bone.
Jahnke W, Bold G, Marzinzik AL, Ofner S, Pelle X, Cotesta S, Bourgier E, Lehmann S, Henry C, Hemmig R.
Angewandte Chemie, International Edition. 2015; 54(48): 14575-14579.
Binding or Bending: Distinction of allosteric Abl kinase agonists from antagonists by an NMR-based conformational assay.
Jahnke W, Grotzfeld RM, Pelle X, Strauss A, Fendrich G, Cowan-Jacob SW, Cotesta S, Fabbro D, Furet P, Mestan J, Marzinzik AL.
J. Am. Chem. Soc. 2010; 132(20): 7043-7048.
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