Journal
CHEMISTRY-A EUROPEAN JOURNAL
Volume 18, Issue 34, Pages 10562-10570Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.201201507
Keywords
drug design; dynamic covalent chemistry; enzymes; hydrazones; inhibitors
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Funding
- CRUK
- EastChem
- EPSRC
- Cancer Research UK [6950] Funding Source: researchfish
- Engineering and Physical Sciences Research Council [EP/G007519/2] Funding Source: researchfish
- EPSRC [EP/G007519/2] Funding Source: UKRI
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A bivalent dynamic covalent chemistry (DCC) system has been designed to selectively target members of the homodimeric glutathione-S-transferase (GST) enzyme family. The dynamic covalent libraries (DCLs) use aniline-catalysed acylhydrazone exchange between bivalent hydrazides and glutathione-conjugated aldehydes and the bis-hydrazides act as linkers to bridge between each glutathione binding site. The resultant DCLs were found to be compatible and highly responsive to templating with different GST isozymes, with the best results coming from the M and Schistosoma japonicum (Sj) class of GSTs, targets in cancer and tropical disease, respectively. The approach yielded compounds with selective, nanomolar affinity (Ki=61 nM for mGSTM1-1) and demonstrates that DCC can be used to simultaneously interrogate binding sites on different subunits of a dimeric protein.
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