Antitumour agents as inhibitors of tryptophan 2,3-dioxygenase

Area of Science:

• Biochemistry
• Immunology
• Pharmacology

Background:

• Tryptophan 2,3-dioxygenase (TDO) plays a critical role in cancer by suppressing anti-tumor immune responses.
• TDO activity promotes tumor cell survival and proliferation, highlighting its significance in cancer biology.
• There is a therapeutic need for specific TDO inhibitors to counteract its pro-cancer effects.

Purpose of the Study:

• To screen a large compound library for novel TDO inhibitors.
• To evaluate the anti-cancer properties of identified TDO inhibitors.
• To assess the selectivity of identified inhibitors against indoleamine 2,3-dioxygenase (IDO).

Main Methods:

• Screening of approximately 2800 compounds from the National Cancer Institute (NCI) USA library.
• In vitro enzyme inhibition assays to determine inhibition constants (Ki) for TDO and IDO.
• Assessment of anti-tumor properties by testing compound efficacy against various cancer cell lines.

Main Results:

• Seven potent TDO inhibitors were identified, with inhibition constants in the nanomolar to low micromolar range.
• All identified compounds demonstrated anti-tumor activity, effectively killing cancer cell lines.
• NSC 36398 (dihydroquercetin/taxifolin) was identified as the first TDO-selective inhibitor, with an in vitro Ki of approximately 16 μM.

Conclusions:

• The study successfully identified novel TDO inhibitors with significant anti-cancer potential.
• NSC 36398 represents a promising lead compound due to its TDO selectivity.
• These findings support the development of TDO inhibitors as a therapeutic strategy in cancer treatment.