448 Discovery of clinical candidate IK-175, a selective orally active AHR antagonist

Abstract

BackgroundAryl Hydrocarbon Receptor (AHR) is a transcription factor that regulates the activity of multiple innate and adaptive immune cells subsequent to binding to a diverse set of endogenous and exogenous ligands. One such endogenous AHR ligand is kynurenine, generated from the precursor tryptophan by indoleamine-pyrrole 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2). Binding of kynurenine to AHR leads to a net immunosuppressive tumor microenvironment. In addition, increased levels of serum kynurenine are associated with resistance to checkpoint inhibitors. Given that kynurenine can be generated by both IDO1 and TDO2 and that AHR is activated by multiple other endogenous ligands, AHR inhibition provides a novel and ideal approach to overcome immunosuppression in a broad range of cancers.MethodsWe sought to identify an orally active AHR antagonist as an immunomodulatory agent for the treatment of solid tumors. Lead optimization efforts identified IK-175 as an AHR antagonist with a favorable ADME and pharmacokinetic profile in preclinical species.ResultsIK-175 inhibits AHR activity in rodent and human cancer cell lines as well as human and nonhuman primate primary immune cells, with concentration dependent effects on AHR target gene expression and cytokine release. IK-175 is inactive in a broad panel of kinases, receptors, and transporters. Orally administered IK-175 dose-dependently blocks ligand stimulated-AHR activation of Cyp1a1 transcription in liver and spleen, demonstrating on-target in vivo activity in mice. IK-175 alone and in combination with an anti-PD-1 antibody demonstrates significant antitumor activity in syngeneic mouse models of colorectal cancer (CT26.WT) and melanoma (B16-IDO1). In addition, IK-175 in combination with liposomal doxorubicin demonstrates antitumor activity in syngeneic mouse models of colorectal cancer (CT26.WT and MC38).ConclusionsThese studies provide rationale for targeting AHR in cancer patients. Ikena will evaluate the anti-tumor activity of IK-175 as a single agent in cancers with activated AHR and in combination with other therapies. Overall, our data demonstrates that IK-175 is a selective orally active AHR antagonist that inhibits tumor growth and reverses immune suppression in mouse tumors models. IK-175 is currently being evaluated in a Phase 1 clinical trial in patients with advanced solid tumors and urothelial carcinoma (Clinicaltrials.gov NCT04200963).