LODI "Lead Optimization of HDAC6/Hsp90 Dual Inhibitors: identification of a drug candidate against metastatic castrate-resistant prostate cancer"

Prostate cancer (PC) is the second more common cancer in men, representing the 15% of all tumors. Although current treatments can be effectiveat early stages of PC, they are not effective against metastatic castrate-resistant prostate cancer (CRPC). The molecular and genetic complexity ofadvanced-stage and CRPC suggest that therapeutic advantages can be obtained by targeting multiple oncogenic pathways with a single drugmolecule. The possibility to develop compounds able to simultaneously modulate the activity of multiple disease-relevant targets present severaladvantages compared to single-target and combination therapies, in line with the polypharmacology concept. Notably, several evidences indicatethat the combined inhibition of Heat Shock Protein 90 (Hsp90) and Histone Deacetylase 6 (HDAC6) may represent a promising strategy to treatadvanced-stage and CRPC, their activities being mutually involved in the regulation of multiple pathways implicated in disease progression. Inparticular, HDAC6 regulates the androgen receptor activity mainly through acetylation/deacetylation of Hsp90, and combination of Hsp90 andHDAC inhibitors is reported to provide impressive synergistic effects. In addition, administration of HDAC inhibitors is known to resensitizeresistant cells towards clinically relevant Hsp90 inhibitors. Fuelled by these evidences, our previous work focused on the design, synthesis and biological evaluation of dual inhibitors of HDAC6 and Hsp90,resulting in the identification of potent and selective dual compounds. In the present project we aim at performing the lead optimization of theidentified Hsp90/HDAC6 dual inhibitors, in order to obtain an innovative drug candidate against CRPC. The project is organized into three Tasks:Task1) in vitro preclinical characterization of the lead compounds; Task2) optimization of the dual inhibitors through in silico design, chemicalsynthesis and in vitro enzyme and cell-based assays, and; Task3) in vivo efficacy and full PK evaluation of the most promising drug candidate.Task1 and Task2 will be performed iteratively until a candidate suitable for full in vivo characterization will be obtained. The lead optimization work prospected in this project could provide significant therapeutic advantages to fight advanced stage and CRPC.Importantly, Hsp90/HDAC6 dual inhibitors would act through a completely new mechanism of action, potentially providing improved therapeuticbenefits with respect to current therapies. Moreover, the preclinical optimization of Hsp90/HDAC6 dual inhibitors may have a significant impact onthe possibility to obtain more effective and safer drugs. While the combination of individual Hsp90 and HDAC6 inhibitors is likely to result inunwanted off-target toxicities and incompatible pharmacokinetic profiles, a single molecule with dual activity would provide a better, less toxic andmore clinically amenable therapeutic strategy against advanced-stage and CRPC.