IMPDH Inosine monophosphate dehydrogenase inhibitors

JAG Cox, D Barros, L Ballell, GS Besra, Singh, Mizrahi, Park, Boshoff
Chemical Class:

Phenotypic screening with a biased target-specific screen. The inosine monophosphate dehydrogenase (IMPDH) protein GuaB2 has been identified as a drugable target in Mycobacterium tuberculosis, however previously identified compounds lack the desired characteristics necessary for further development into lead-like molecules. This study has identified 7 new chemical series from a high-throughput resistance based phenotypic screen using Mycobacterium bovis BCG over-expressing GuaB2. Hit compounds from the ‘TB Box’ set were identified in a single shot high-throughput screen, validated by dose response and subjected to further biochemical analysis. The compounds were assessed using molecular docking experiments,
providing a platform for their further optimisation using medicinal chemistry.

Indazole sulphonamides identified by high-throughput screening of >100,000 synthetic compounds for activity against Mycobacterium tuberculosis (Mtb). These noncytotoxic compounds triggered a slow lysis of Mtb cells. Bbiochemical validation confirmed direct inhibition of IMPDH.   Advanced lead compounds in this series with acceptable pharmacokinetic properties failed to show efficacy in acute or chronic murine models of tuberculosis.

VCC234718, a molecule with growth inhibitory activity against Mycobacterium tuberculosis (Mtb), was identified by phenotypic screening of a 15344-compound library.  inosine monophosphate dehydrogenase, GuaB2, which was subsequently validated to be the primary molecular target of VCC234718 in Mtb.