Plasmodium bromodomain PfBDP4; A Target Enabling Package

<p>There are 8 bromodomain-containing proteins in each annotated Plasmodium genome, with only one containing dual bromodomains (BRDs) – i.e. a total of 9 BRDs. In collaboration with SGC Oxford, we have expressed, purified and crystallized the BRDs in PfBDP1, PfBDP3, PfBDP4 (namely PfBDP4B) and PfGCN5. By screening all four against a focused BRD inhibitor library (SGC Oxford) using the DSF assay, we identified a small number of hits that were subsequently validated and quantitatively assessed using ITC. Two similar compounds with the dihydropteridinone scaffold, namely BI2536 and BI6727, stood out as potent inhibitors of PfBDP4B (both with Kd below 200 nM). We further collaborated with U of Melbourne to test them against Pf3D7 and found them capable of inhibiting blood stage development at sub-micromolar concentrations. Analysis of the co-structure of PfBDP4B+BI2536 suggests the possibility of increasing the potency and selectivity of inhibition.</p

Plasmodium bromodomain PfBDP4; A Target Enabling Package

<p>There are 8 bromodomain-containing proteins in each annotated Plasmodium genome, with only one containing dual bromodomains (BRDs) – i.e. a total of 9 BRDs. In collaboration with SGC Oxford, we have expressed, purified and crystallized the BRDs in PfBDP1, PfBDP3, PfBDP4 (namely PfBDP4B) and PfGCN5. By screening all four against a focused BRD inhibitor library (SGC Oxford) using the DSF assay, we identified a small number of hits that were subsequently validated and quantitatively assessed using ITC. Two similar compounds with the dihydropteridinone scaffold, namely BI2536 and BI6727, stood out as potent inhibitors of PfBDP4B (both with Kd below 200 nM). We further collaborated with U of Melbourne to test them against Pf3D7 and found them capable of inhibiting blood stage development at sub-micromolar concentrations. Analysis of the co-structure of PfBDP4B+BI2536 suggests the possibility of increasing the potency and selectivity of inhibition.</p

Plasmodium bromodomain PfBDP4; A Target Enabling Package

<p>There are 8 bromodomain-containing proteins in each annotated Plasmodium genome, with only one containing dual bromodomains (BRDs) – i.e. a total of 9 BRDs. In collaboration with SGC Oxford, we have expressed, purified and crystallized the BRDs in PfBDP1, PfBDP3, PfBDP4 (namely PfBDP4B) and PfGCN5. By screening all four against a focused BRD inhibitor library (SGC Oxford) using the DSF assay, we identified a small number of hits that were subsequently validated and quantitatively assessed using ITC. Two similar compounds with the dihydropteridinone scaffold, namely BI2536 and BI6727, stood out as potent inhibitors of PfBDP4B (both with Kd below 200 nM). We further collaborated with U of Melbourne to test them against Pf3D7 and found them capable of inhibiting blood stage development at sub-micromolar concentrations. Analysis of the co-structure of PfBDP4B+BI2536 suggests the possibility of increasing the potency and selectivity of inhibition.</p