ACK1 Inhibitor

(R)-9b: A New ACK1 Inhibitor

Limited Efficacy of Existing AR-antagonists

Androgen Receptor (AR) plays a paramount role in the onset and progression of prostate cancer (PC), hence patients are often treated with androgen deprivation therapy (ADT) or AR antagonists, which provides immediate palliative benefits. However, the majority of PC patients progress to a lethal stage of disease, referred to as Castration Resistant Prostate Cancer (CRPC). Abiraterone and Enzalutamide are the 'second generation' of AR antagonists, which are effective only short term — most patients relapse within 1-2 years. (R)-9b is the next generation of a new class of small molecule inhibitor that can overcome Enzalutamide and Abiraterone resistance, a critical unmet need.

ACK1, a crucial regulator of CRPC tumor growth

ACK1 is a structurally unique non-receptor tyrosine kinase upregulated in ~25% of prostate adenocarcinomas and almost 50% of CRPCs. 10 out of 13 CRPCs exhibited 5- to >100-fold ACK1 mRNA overexpression. Activated ACK1 correlates positively with disease progression and poor prognosis. ACK1 interacts with AR, depositing epigenetic marks that upregulate AR expression. (R)-9b erases these marks, causing global loss of AR and AR-V7 expression, compromising Enz/Abi-resistant tumor growth.

(R)-9b, a first-in-class 'dual' inhibitor with immune modulatory activity

(R)-9b exhibited a unique activity — it activated CD8+ T cells in the tumor microenvironment, causing a robust immune response against tumors. This makes it a rare 'dual' inhibitor that suppresses AR expression in tumor cells while also activating effector T cells. (R)-9b activated T cells isolated from blood of Abiraterone and Enzalutamide-treated CRPC patients, indicating a new strategy to sensitize patients to ICB therapy.

Oral inhibitor: IND & Phase I clinical trial (PHAROS)

Pre-IND studies with (R)-9b revealed it to be a safe molecule for clinical trials and effective when administered orally. No ACK1 inhibitor has ever been tested in clinical trials before. PHAROS, a human Phase I clinical trial, has started under IND #167907 — the first-in-human trial to assess safety and tolerability of the novel ACK1 inhibitor (R)-9b in patients with prostate cancer.