Current state on tryptophan 2,3-dioxygenase inhibitors: a patent review

ABSTRACT

Introduction: Tryptophan-2, 3-dioxygenase (TDO2) is a tryptophan-degrading enzyme constitutively expressed in the liver and to a lesser extend in the brain. Before its link to cancer immunotherapy was discovered in 2011, the search for TDO2 inhibitors was initially driven by depression therapy. In the recent years, TDO2 has drawn an increasing attention as a promising target in both cancer and neuropsychiatric diseases.

Areas covered: Patent literature regarding Tryptophan-2, 3-dioxygenase inhibitors is reviewed. Compounds are categorized by chemical structure. Representative examples of each category are presented with their inhibitory activity and, when available, structure-activity relationships. Data from patent literature is deepened with relevant peer-reviewed literature.

Expert opinion: Very few selective and potent inhibitors were to this day reported and there are currently no TDO2 inhibitors in clinical trials. Despite the challenges in their discovery, the search for TDO2 inhibitors is a very active area of research, as such molecules may prove to be of great interest in not only cancer immunotherapy drug arsenal, but also in neurodegenerative diseases.

KEYWORDS:

• Kynurenine pathway
• immunotherapy
• anticancer
• tryptophan 2
• 3-dioxygenase

Article highlights

• TDO2 is a target that has drawn increasing attention in both cancer immunotherapy and neuropsychiatric disorders over the past decade.

• The first application regarding TDO2 inhibitors was published in 2014.

• This article reviews existing patent literature as well as relevant peer-reviewed literature on TDO2 inhibitors.

• It exemplifies representative compounds for each chemical class of inhibitors with, when available, their IC₅₀s and structure-activity relationships data.

• The development of TDO2-selective and potent inhibitors is the key to fully understood the implications of the kynurenine pathway.

• The small size and lipophilicity of TDO2’s active pocket may represent a challenge for the discovery of drug-like inhibitors.

This box summarizes key points contained in the article.

Declaration of interest

A. Kozlova is a research fellow from the Belgian ‘Fonds de la Recherche Scientifique – FNRS.’ The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper received funding from Fonds National de recherche Scientifique (Belgium) and Télévie.