ralaniten acetate (EPI-506)

In addition, these studies revealed a unique and strong induction of expression of the metallothionein family of genes by ralaniten by a mechanism independent of AR and dependent on MTF1, thereby suggesting this may be an off-target. Due to the relatively high doses that may be encountered clinically with AR-NTD inhibitors, identification of off-targets may provide insight into potential adverse events, contraindications, or poor efficacy.

Androgen receptor (AR) has essential roles in the growth of prostate cancer and some breast cancers. Importantly, sequential combination treatments with palbociclib administered first then followed by EPI-7170, resulted in more cells accumulating in G1 and less cells in S phase than concomitant combination which was presumably because each inhibitor has a unique mechanism in modulating the cell cycle in cancer cells. Together these data support that the combination therapy was more effective than individual monotherapies to reduce tumor growth by targeting different phases of the cell cycle.

Combination of Pin1 inhibitor with ralaniten promoted cell cycle arrest and had improved antitumor activity against CRPC xenografts in vivo compared to individual monotherapies. These findings support the rationale for therapy that combines a Pin1 inhibitor with ralaniten for treating CRPC.

Resistance of castration-recurrent prostate cancer (CRPC) to enzalutamide and abiraterone involves the expression of constitutively active, truncated androgen receptor (AR) splice variants (AR-Vs) that lack a C-terminal ligand-binding domain (LBD). Both full-length AR and truncated AR-Vs require a functional N-terminal domain (NTD) for transcriptional activity thereby providing rationale for development of ralaniten (EPI-002) as a first-in-class antagonist of the AR-NTD...In addition, this drug enhanced the anti-tumor effect of enzalutamide in enzalutamide-resistant CRPC preclinical models. Thus, a combination therapy targeting both the NTD and LBD of AR, and thereby blocking both full-length AR and AR-Vs, has potential for the treatment of enzalutamide-resistant CRPC.

Unfortunately, ADT, antiandrogens, and abiraterone increase expression of constitutively active splice variants of AR (AR-Vs) which regulate DNA damage repair leading to resistance to radiotherapy. An additive inhibitory effect on proliferation of enzalutamide-resistant cells was achieved with a combination of ralaniten compounds with ionizing radiation. Ralaniten and EPI-7170 sensitized prostate cancer cells that express full-length AR and AR-Vs to radiotherapy whereas enzalutamide had no added benefit.

Selective inhibition of the N-terminal domain (NTD) of the AR can inhibit its transcriptional activity even in the presence of LBD-driven resistance.  EPI-7386 is a second-generation AR NTD inhibitor with excellent potency, metabolic stability and preclinical efficacy compared to first generation AR NTD inhibitor (“aniten”) EPI-506...EPI-7386 was able to induce tumor regression in CRPC xenografts and show single-agent superiority to enzalutamide (ENZ) in ENZ resistant models with a wide therapeutic range... EPI-7386 is a second-generation AR NTD inhibitor with excellent potency and metabolic stability.  Based on the results of preclinical efficacy models, this agent demonstrates the potential to be developed clinically both as a single agent in the setting of anti-androgen clinical resistance as well as in combination therapy with anti-androgens in earlier stages of the disease. Source of Funding: ESSA Pharmaceuticals Corp

Therefore, we tested an analogue of ralaniten (EPI-045) which was resistant to glucuronidation and demonstrated superiority to ralaniten in our resistant model. These data support that analogues of ralaniten designed to mitigate glucuronidation may optimize clinical responses to AR-NTD inhibitors.

The discovery of small molecules, including the libraries used, proven binders to the AR-NTD, and site of interaction of these small molecules in the AR-NTD are presented along with discussion of the Phase I clinical trial.Expert opinion: The lack of drugs in the clinic that directly bind IDPs/IDRs reflects the difficulty of targeting these proteins and obtaining specificity. However, it may also point to an inappropriateness of too closely borrowing concepts and resources from drug discovery to folded proteins.