Discovery of Rogocekib (CTX-712): A Potent and Selective CLK Inhibitor for Cancer Treatment

Area of Science:

• Medicinal Chemistry
• Oncology
• Molecular Biology

Background:

• Dysregulated RNA splicing is implicated in various diseases, particularly cancers.
• Cdc2-like kinase (CLK) inhibitors offer a therapeutic strategy by modulating RNA splicing.
• Targeting CLK provides a novel approach for cancer treatment.

Purpose of the Study:

• To discover and characterize Rogocekib (CTX-712), a novel CLK inhibitor.
• To evaluate the therapeutic potential of CTX-712 in preclinical cancer models.
• To investigate the mechanism of action of CTX-712 on RNA splicing.

Main Methods:

• Structure-based drug design and scaffold hopping were employed.
• Medicinal chemistry optimization led to the 1H-imidazo-[4,5-b]-pyridine series.
• In vitro and in vivo assays were used to assess efficacy and mechanism.

Main Results:

• CTX-712 treatment reduced serine- and arginine-rich protein phosphorylation dose-dependently.
• Potent in vitro cell growth suppression was observed.
• Significant in vivo antitumor activity was demonstrated in a lung cancer xenograft model.

Conclusions:

• Rogocekib (CTX-712) is a promising CLK inhibitor with demonstrated efficacy.
• CTX-712 exhibits potential as a therapeutic agent for cancers, especially those with RNA splicing alterations.
• Further clinical development of CTX-712 is warranted for cancer therapy.