AhR (IDE697)

Overview

Our precision medicine approach in immuno-oncology includes biomarker-enabled targeted therapies directed to biological pathways known to be immunosuppressive in the tumor microenvironment. IDE697 is a potentially first-in-class, potent antagonist of aryl hydrocarbon receptor (AhR), a receptor for metabolites such as Kynurenine (Kyn).

Tumors with Activated AhR Pathway

AhR Pathway and Immuno-Suppression in Solid Tumors

The AhR pathway is a well-studied immuno-regulatory pathway active in many tumors. Activated AhR mediates nuclear factor kappa-light-chain-enhancer of activated B cells, or NFkB, which regulates immune responses. Activated AhR also translocates to the nucleus, and alters immune gene transcription, leading to increases in the numbers of regulatory T-cells, or Treg, which results in local immunosuppression.

AhR is activated in tumors by kynurenine, an endogenous agonist. IDO and TDO are enzymes which convert tryptophan to kynurenine. Literature suggests that Kyn plays an important role in tumor growth and mechanisms of immune escape, and that high Kyn levels correlate with advanced grade in breast, glioma and prostate tumors.

Summary of Preclinical Data

IDE697 is a potent and selective small molecule antagonist of AhR. Preclinical data illustrates that IDE697 antagonizes AhR across multiple species and blocks ligand-dependent translocation of AhR to the nucleus, thus preventing it from functioning as a transcriptional activator. Immuno-profiling data shows that IDE697 inhibits the suppressive activity of human T-regulatory and M2 macrophages and restores cytolytic T-effector cell activity.

IDEAYA plans to conduct a biomarker focused, Phase 1 clinical trial to determine safety and preliminary efficacy of IDE697 in patients with tumors in which the AhR pathway is activated.