(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, these ADTs are ineffective long term, and the majority of the PC patients progress to a lethal stage of the disease, referred to as the Castration Resistant Prostate Cancer (CRPC).

Abiraterone and Enzalutamide, are the `second generation' of AR antagonists, which are effective for short term. Unfortunately, most patients relapse within 1-2 years. Significantly, these relapsed patients exhibit renewed AR and AR splice variant expression, developing resistance.

(R)-9b is the next generation of inhibitor that can overcome Enzalutamide and Abiraterone resistance, a critical unmet need.

Cancer Cell, 2017
Structure of ACK1 kinase ATP-binding pocket with (R)-9b
ACK1, a crucial regulator of CRPC tumor growth

ACK1 is a structurally unique non-receptor tyrosine kinase that is upregulated in ~25% of prostate adenocarcinomas and almost 50% of CRPCs. Importantly, 10 out of 13 CRPCs exhibited 5- to >100-fold ACK1 mRNA overexpression. Moreover, expression of activated ACK1 not only correlates positively with the progression of disease to CRPC stage, but also revealed that patients that display moderate to strong staining of activated ACK1 have poor prognosis.

Mechanistic studies reveal that ACK1 tyrosine kinase interacts with AR, causing its phosphorylation and acetylation. The modified AR interacts with ACK1, and ACK1/AR complex deposit novel epigenetic marks, histone H4 Tyr88-phosphorylation (pY88-H4) directly upstream of AR gene locus, upregulating its expression.

ACK1 inhibitor, (R)-9b erased pY88-H4 marks causing global loss of AR and AR-V7 expressing, significantly compromising Enz/Abi-resistant tumor growth.

Science Translational Medicine, 2022
(R)-9b, a first-in-class `dual' inhibitor with Immune modulatory activity

Significantly, (R)-9b exhibited an unique activity- it activated CD8+ T cells in tumor microenvironment, causing robust immune response against tumors. This novel immune modulatory activity makes this compound a rare `dual' inhibitor that not only suppresses AR expression in tumor cells but also activate effector T cells to target cancer cells.

Prostate tumors exhibit ICB (immune checkpoint blockade) resistance. (R)-9b was able to activate T cells isolated from blood of Abiraterone and Enzalutamide treated CRPC patients. This is a significant data to indicate a new strategy to activate immune cells in patients with prostate cancer and sensitize them to ICB therapy.

Nature Communications, 2022
(R)-9b, Oral inhibitor: IND & Phase I Clinical Trial (PHAROS)

Pre-IND Studies with (R)-9b or Mahatinib revealing it to be a `Safe' molecule for Clinical trials. Significantly, it is effective when administered orally.

No ACK1 inhibitor has ever been tested in clinical trials.

PHAROS: A human clinical trial (phase I) is expected to be in early 2025.

Phase 1, First in Human Trial to Assess Safety and Tolerability of the Novel ACK1 Inhibitor (R)-9b in Patients with Prostate Cancer (acronym: PHAROS)