Background: The molecular and genetic complexity of advanced-stage and castrate-resistant prostate cancer (CRPC) suggests that targeting a single oncogenic pathway may have little impact on overall patient survival. Several evidences indicate that inhibition of the molecular chaperone heat shock protein 90 (Hsp90) and histone deacetylase 6 (HDAC6) enzymes is a promising strategy to treat advanced-stage and CRPC. Hsp90 and HDAC6 are biochemically and functionally linked, HDAC6 regulates androgen receptor activity mainly through acetylation/deacetylation of Hsp90, and combination of Hsp90 and HDAC inhibitors results in impressive synergistic effects. Moreover, administration of HDAC inhibitors is able to resensitize resistant cells towards clinically relevant Hsp90 inhibitors. The close interplay between Hsp90 and HDAC6 make these two proteins excellent candidates for a rational multi-target drug discovery approach.
Hypothesis: Our proposal relies on the hypothesis that a single molecule with dual Hsp90/HDAC6 inhibitory activity may represent an innovative and more effective pharmacological strategy to treat advanced stage PC and CRPC, for which no therapeutic option is currently available. While the combination of individual Hsp90 and HDAC6 inhibitors is likely to have additive off-target toxicities and perhaps incompatible pharmacokinetic profiles that will make their routine use in patients problematic, a single molecule with dual activity would provide a better, less toxic and more clinically amenable therapeutic strategy against advanced-stage PC and CRPC.
Aims: The aim of this project is to discover and optimize small molecular weight and drug-like dual inhibitors of HDAC6 and Hsp90, two molecular targets implicated in PC progression. We aim at demonstrating that such multi-target strategy is feasible and can be translated to inhibition of advanced stage PC and CRPC in vitro and in vivo. In the long term, we aim at identifying a novel polypharmacological strategy that can be successfully developed for clinical use.
Experimental design: The project is organized into five research tasks: i) molecular modelling and computational design of Hsp90 and HDAC6 dual inhibitors, ii) chemical synthesis of the most interesting compounds emerging from the drug design work, iii) enzyme and cell-based assays on the synthesized compounds, iv) in vivo studies and pharmacokinetics evaluation of selected inhibitors, v) evaluation of the best compounds on organoids.
Expected results: We expect that the experiments proposed here will identify novel anti-cancer compounds specifically targeting advanced stage and CRPC through dual inhibition of Hsp90 and HDAC6.
Impact on Cancer: Prostate cancer is the second more common cancer in men. Depending on stage and grade, a huge part of patients has androgen-independent PC (AIPC) or becomes hormone refractory (ARPC). Targeting multiple signalling pathways with a single drug molecule able to hit multiple oncoproteins is a very promising strategy in anticancer drug discovery. The identification and preclinical optimization of dual Hsp90/HDAC6 inhibitors prospected in this application may have a significant impact on the possibility to obtain more effective and safer drugs. Because there is still no curative treatment for CRPC, this project could represent an important step toward a pharmacologic approach to treat this disease.