Development of Novel Drug Candidate against Prostate Cancer

Among men, prostate cancer is the third leading cause for death out of all cancers. Despite remarkable progress in premature diagnostics and treatment, prostate cancer stands as one of the most devastating human diseases. The development of anti-prostate cancer drugs remains urgent.

Smurf2 is an E3 ubiquitin ligase sufficient in the regulation of protein homeostasis. Previous studies have demonstrated that the distribution of Smurf2 is different in both normal and cancer tissues: nuclear Smurf2 is a negative regulator of RNF20 that causes modifications in the epigenetic landscape, in particularly in monoubiquitination of histone H2B. The H2B histone packs and orders the DNA and contributes in gene expression regulation and DNA damage response. On the other hand, cytosolic Smurf2 has been reported to reduce the steady-state of Axin and GSK3b (two negative regulator of Wnt/β-catenin signaling). The activation of this signaling pathway leads to uncontrolled cell growth.

Smurf2 is a member of HECT-type family of E3s. This family is characterized by a common modular organization: an N-terminal C2 domain, two to four WW domains, and a C-terminal HECT domain. The HECT domain is responsible for the attachment of ubiquitin moieties to target proteins. We hypothesized that targeting of Smurf2 for inactivation might affect the ability of cancer cells to proliferate and/or withstand anticancer treatments. Based on computational modeling several Smurf2 HECT domain specific binders (activators and inhibitors) were designed and synthetized. Then, in vitro evaluation in prostate cancer models showed that two novel peptidomimetic compounds were active at nM concentration range.

This novel approach for the possible treatment of prostate cancer which is based on the modulation of Smurf2 function has not been reported yet.