Design and Synthesis of Hsp90 Inhibitors with B‐Raf and PDHK1 Multi‐Target Activity. Issue 12 (11th October 2021)

• Record Type: Journal Article
• Authors: Pinzi, Luca; Foschi, Francesca; Christodoulou, Michael S.; Passarella, Daniele; Rastelli, Giulio
• Is Part Of: ChemistryOpen. Volume 10:Issue 12(2021)
• Page Start: 1177
• Page End: 1185
• Publication Date: 2021-10-11
• Subjects: docking -- in vitro assays -- molecular dynamics -- multi-target ligands -- polypharmacology; Chemistry -- Periodicals; 540; 540.5
• DOI: 10.1002/open.202100131
• Languages: English
• ISSNs: 2191-1363

Abstract

Abstract: The design of multi‐target ligands has become an innovative approach for the identification of effective therapeutic treatments against complex diseases, such as cancer. Recent studies have demonstrated that the combined inhibition of Hsp90 and B‐Raf provides synergistic effects against several types of cancers. Moreover, it has been reported that PDHK1, which presents an ATP‐binding pocket similar to that of Hsp90, plays an important role in tumor initiation, maintenance and progression, participating also to the senescence process induced by B‐Raf oncogenic proteins. Based on these premises, the simultaneous inhibition of these targets may provide several benefits for the treatment of cancer. In this work, we set up a design strategy including the assembly and integration of molecular fragments known to be important for binding to the Hsp90, PDHK1 and B‐Raf targets, aided by molecular docking for the selection of a set of compounds potentially able to exert Hsp90‐B‐Raf‐PDHK1 multi‐target activities. The designed compounds were synthesized and experimentally validated in vitro . According to the in vitro assays, compounds 4 a, 4 d and 4 e potently inhibited Hsp90 and moderately inhibited the PDHK1 kinase. Finally, molecular dynamics simulations were performed to provide further insights into the structural basis of their multi‐target activity. Abstract : Multitasking ligands : A set of ad hoc ligands has been designed by integrating molecular fragments of known inhibitors of anticancer drug targets. The compounds were docked into the respective targets, and six derivatives were synthesized to be in vitro tested. Molecular dynamics studies were finally performed to provide further insights into the structural basis of the experimentally observed activities.