Advances in the discovery and development of selective heme-displacing IDO1 inhibitors

ABSTRACT

Introduction

Indoleamine 2,3-dioxygenase 1 (IDO1) has been considered as an attractive intracellular target for the development of small-molecule cancer immunotherapy. Results in human clinical studies indicated that the first-generation IDO1 inhibitor epacadostat lacked anticancer activity when combined with the anti-PD-1 antibody pembrolizumab. Epacadostat inhibits IDO1 activity by forming a tertiary IDO1-heme-inhibitor complex. Recently, IDO1 inhibitors capable of displacing the heme group to form a binary high-affinity complex have been discovered and investigated in humans.

Areas covered

Structures, mode of action, preclinical activities, and status of clinical development are discussed and compared between the two classes of IDO1 inhibitors that bind to IDO1 protein in the presence (holo-IDO1) or absence (apo-IDO1) of the heme group, respectively. By selectively displacing the heme from IDO1 enzymes, apo-IDO1 inhibitors demonstrate high target selectivity, durable target engagement, and exceptional potency in cellular assays. Data from publications, patent disclosures, and conference proceedings as recent as 2019 are analyzed and summarized.

Expert opinion

The outcomes in cancer patients for the first-generation IDO1 inhibitors were disappointing. However, the unique mode of action by the heme-displacing IDO1 inhibitors might help their successful clinical translation and provide a novel class of anticancer drugs for cancer immunotherapy.

KEYWORDS:

• Cancer immunotherapy
• heme-displacing IDO1 inhibitor
• IDO1
• immune checkpoint
• kynurenine
• PD-1/-L1
• tumor microenvironment

Article highlights

• IDO1 plays an important role in shaping the immunosuppressive TME.

• The first-generation heme-binding IDO1 inhibitors including epacadostat failed to demonstrate anticancer efficacy in patients with advanced cancer either as a single agent or in combination with ICIs.

• The heme-displacing IDO1 second-generation inhibitors are superior in terms of potency, selectivity, and duration of decreasing the levels of Kyn in circulation and tumors.

• The outcomes from the clinical studies of BMS-986205, as well as other heme-displacing IDO1 inhibitors, will inform the future directions of targeting IDO1 for cancer immunotherapy.

• The role of TDO2 in immunooncology remains to be clarified, which will provide guidance for rational design of IDO1-selective or IDO1/TDO2 dual inhibitors.

This box summarizes the key points contained in the article.

Declaration of interest

The author has no 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 manuscript has not been funded.