Examples of Fragments Progressed into Nanomolar Leads

EXAMPLES OF FRAGMENTS PROGRESSED INTO NANOMOLAR LEADS 

Over the last three years there have been a significant number of reports in which weakly active fragment hits have been identified and progressed into potent lead compounds (potency 1 pM) and Table 1 summarises these reports. The table is ordered with the most challenging targets first. 

Cell-based ELISA assay pGSK3 3 IC50 = 1.9 pM 

Caspase 1 (Table 1, entry 4) Another protease screened using fragments is caspase 1. Using a tethering approach (described earlier) active sub-site binders were identified and then linked to produce a sub-micromolar inhibitor 24. Further optimisation by rigidifying the linker produced a ligand-efficient nanomolar inhibitor 25 [38]. 

HCV IRES (Table 1, entry 6) A mass spectroscopy-based fragment approach was used to identify the weak binder 29 to the ribosome HA sub-domain of hepatitis C (HCV IRES). Conventional optimisation led to a sub-micromolar lead 30 [41]. 

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Examples of Fragments Progressed into Nanomolar Leads 435... 

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