Long-Acting Tumor-Activated Prodrug of a TGFβR Inhibitor

Area of Science:

• Oncology
• Immunology
• Pharmacology

Background:

• Transforming growth factor beta (TGFβ) signaling inhibition combined with checkpoint blockade enhances antitumor immunity in preclinical models.
• TGFβ receptor (TGFβR) inhibitors face clinical limitations due to on-target cardiovascular adverse effects.

Purpose of the Study:

• To develop tumor-activated prodrugs of a TGFβR1 inhibitor to restrict its activity to tumor tissues.
• To improve the therapeutic index of TGFβR1 inhibitors by minimizing systemic exposure and off-target toxicity.

Main Methods:

• Synthesis of TGFβR1 inhibitor prodrugs by linking the inhibitor to a serine protease substrate and a fatty acid chain.
• In vitro and in vivo studies to assess selective metabolism in tumor tissues versus heart and blood.
• Pharmacokinetic and efficacy studies of the most promising prodrug in mouse models.

Main Results:

• Prodrugs demonstrated selective metabolism in tumor tissues, leading to a favorable tumor-to-heart drug ratio.
• Compound 10, a highly tissue-selective prodrug, showed comparable anti-tumor efficacy to the parent inhibitor.
• Once-weekly administration of compound 10 resulted in reduced systemic exposure of the active TGFβR1 inhibitor.

Conclusions:

• Tumor-activated prodrugs of TGFβR1 inhibitors can effectively target tumor tissues.
• This strategy significantly reduces systemic exposure and potential cardiovascular toxicity.
• The developed prodrugs offer a promising approach to enhance cancer immunotherapy safety and efficacy.