A molecule inducing androgen receptor degradation and selectively targeting prostate cancer cells

Abstract

Aberrant androgen signaling drives prostate cancer and is targeted by drugs that diminish androgen production or impede androgen–androgen receptor (AR) interaction. Clinical resistance arises from AR overexpression or ligand-independent constitutive activation, suggesting that complete AR elimination could be a novel therapeutic strategy in prostate cancers. IRC117539 is a new molecule that targets AR for proteasomal degradation. Exposure to IRC117539 promotes AR sumoylation and ubiquitination, reminiscent of therapy-induced PML/RARA degradation in acute promyelocytic leukemia. Critically, ex vivo, IRC117539-mediated AR degradation induces prostate cancer cell viability loss by inhibiting AR signaling, even in androgen-insensitive cells. This approach may be beneficial for castration-resistant prostate cancer, which remains a clinical issue. In xenograft models, IRC117539 is as potent as enzalutamide in impeding growth, albeit less efficient than expected from ex vivo studies. Unexpectedly, IRC117539 also behaves as a weak proteasome inhibitor, likely explaining its suboptimal efficacy in vivo. Our studies highlight the feasibility of AR targeting for degradation and off-target effects’ importance in modulating drug activity in vivo.

Sumoylation on its 25th anniversary: mechanisms, pathology, and emerging concepts

“…While further research is needed to precisely clarify the involvement of RNF4 in tumorigenesis, given these conflicting roles, targeted induction of oncoprotein poly-sumoylation or promoting RNF4 STUbL activity might be better therapeutic goals than simply increasing global RNF4 availability. For example, IRC117539 is a novel molecule that binds AR and induces its sumoylation [237]. How IRC117539 promotes AR sumoylation is unclear, yet the treatment results in sumoylation-dependent degradation of AR by the proteasome, inducing massive loss of viability in AR-dependent prostate cancer cells [237].…”

“…For example, IRC117539 is a novel molecule that binds AR and induces its sumoylation [237]. How IRC117539 promotes AR sumoylation is unclear, yet the treatment results in sumoylation-dependent degradation of AR by the proteasome, inducing massive loss of viability in AR-dependent prostate cancer cells [237]. Finally, sumoylation can also indirectly promote degradation of oncoproteins or tumor suppressors by stabilizing their negative regulators, such as in the case of p53 destabilization arising from sumoylation and consequently enhanced activity of the MDM2 ubiquitin E3 ligase [238].…”

Sumoylation of Cas9 at lysine 848 regulates protein stability and DNA binding

“…Next, we used HEK293 cells stably expressing FLAG-Cas9 to perform proximity ligation assays (PLA). PLA is a highly sensitive technique that enables visualization of protein–protein interactions that occur within a proximity of <16 nm and can be used for specific and accurate detection of protein sumoylation and ubiquitylation in situ ( 51 , 52 , 53 ). We used primary antibodies to target FLAG–Cas9 and endogenous SUMOs, followed by incubation with secondary antibodies corresponding to each primary antibody.…”

“…To assess the role of global sumoylation in Cas9 stability, we used ML792, a small molecule inhibitor of the SUMO E1 enzyme that blocks protein sumoylation ( 51 , 54 ). In both HEK293 and HeLa cells, co-treatment with ML792 also caused a significant decrease in the stability of wild-type Cas9, as judged by the protein levels remaining at 24 h of cycloheximide exposure ( Figs 5C and S4A ).…”

Targeting SUMO Signaling to Wrestle Cancer

“…In addition, IRC117539 promotes SUMOylation and ubiquitylation of the androgen receptor (AR) as potential therapy for prostate cancers, reminiscent to As 2 O 3 therapy in APL. IRC117539 reduced cell growth in AR-positive prostate cancer cells, whereas combining IRC117539 with ML-792 left the drug completely ineffective [95]. The abovementioned considerations need to be considered for SUMO inhibition as tailored therapeutic options for a subset of malignancies.…”