Heat shock protein 90 and serine/threonine kinase B-Raf inhibitors have overlapping chemical space

Heat shock protein 90 (Hsp90) and B-Raf are validated targets for anticancer drug discovery. Although there is strong evidence that concomitant inhibition of Hsp90 and B-Raf may provide significant therapeutic benefits, molecules endowed with dual activity against the two targets have not been reported. For the first time, we show that Hsp90 and B-Raf inhibitors have overlapping chemical space and we disclose the first-in-class dual inhibitors. The compounds were identified through a computational strategy especially devised for detecting ligands with dual-target activity. Although the two targets had only remote binding site similarity, we were able to identify dual inhibitors with well-balanced in vitro potencies and relatively low molecular weight. Remarkably, they also inhibited the V600E mutant form of B-Raf with similar potency. This study provides the first direct proof that designing dual ligands of Hsp90 and a kinase is possible, thus opening the way to new interesting possibilities in drug discovery.