Advancements in Cancer Therapy: The Development and Potential of ARN-3261 as a SIK2 Inhibitor

The research presents ARN-3261, an innovative, orally administered small molecule inhibitor of Salt Inducible Kinase 2 (SIK2) and SIK3, which are Ser/Thr kinases pivotal for mitotic spindle formation. SIK2 overexpression is observed in a significant portion of ovarian cancer cases, pointing to its potential as a therapeutic target. SIK2 and SIK3 are also implicated in various other cancers, including breast, prostate, diffuse large B-cell lymphoma, and melanoma.

The study details the discovery of ARN-3261 using homology modeling, fragment-based optimization, and structure-activity relationship analysis. It has been shown to selectively inhibit SIK2 with an IC50 of 92 nM and to be efficacious against ovarian and breast cancer cell lines, both as a single agent and in combination with established chemotherapeutic agents like Paclitaxel and Cisplatin.

In vivo studies in a SKOv3 human ovarian cancer xenograft model demonstrated that ARN-3261 significantly reduced tumor growth in a dose-dependent manner at various concentrations. The compound also displayed favorable pharmacokinetic and pharmacodynamic profiles, as well as promising ADME properties.

Mechanistically, ARN-3261 is suggested to enhance the sensitivity of cancer cells to Paclitaxel by blocking centrosome separation through SIK2 inhibition. The study's positive findings have led to the initiation of IND-enabling GLP toxicology and safety studies, with the aim of advancing ARN-3261 to First-In-Human Phase 1 clinical trials. The presentation will include non-clinical pharmacology data and plans for a Phase 1 proof-of-concept clinical trial.