P1, N=47, Terminated, Bayer | Trial completion date: Dec 2025 --> Jan 2025 | Active, not recruiting --> Terminated; Last patient ongoing on treatment ended the study on 20th January 2025. Hence, the end of study was reached as defined in the protocol.

P1, N=47, Active, not recruiting, Bayer | Trial completion date: Mar 2025 --> Dec 2025 | Trial primary completion date: Mar 2025 --> Jun 2024

No differentially expressed genes (DEGs) were identified in wildtype cells exposed to 1 μM BAY2416964 for 24 h; however, 46.4% of DEGs overlapped between AhrKO and LT-BAY cells including gene regulated cell proliferation. Our data reveal long-term pharmacological inhibition of AHR by BAY2416964 closely resembles AHR loss in a mouse model of breast cancer.

P1, N=0, Withdrawn, Ikena Oncology | Phase classification: P1b --> P1 | N=54 --> 0 | Trial completion date: Jul 2025 --> Apr 2023 | Not yet recruiting --> Withdrawn | Trial primary completion date: Jul 2024 --> Apr 2023

P1, N=47, Active, not recruiting, Bayer | Trial completion date: Dec 2025 --> Mar 2025 | Trial primary completion date: Dec 2025 --> Mar 2025

P1, N=78, Completed, Bayer | Active, not recruiting --> Completed

P1, N=47, Active, not recruiting, Bayer | Recruiting --> Active, not recruiting | N=164 --> 47

At the same time, it increased DNA POLβ protein expression, which indicates increased DNA repair, thus causing a chemopreventive effect. These results provide evidence for the chemopreventive effects of DATS in breast cancer prevention.

P1, N=78, Active, not recruiting, Bayer | Trial completion date: Apr 2025 --> Jan 2024

These findings identify AhR inhibition as a novel therapeutic approach to overcome immune resistance in various types of cancers.

P1, N=164, Recruiting, Bayer | Phase classification: P1b --> P1

We have observed that the AHR protein levels increase in the presence of chloroquine (CQ), an autophagy inhibitor, in a dose-dependent manner...This decrease suppresses the ligand-dependent activation of the AHR target gene transcription, and can be reversed by CQ but not MG132...Suppression of the epithelial-to-mesenchymal transition in A549 cells is observed when the AHR gene is knocked out or the AHR protein level is reduced by 6-AN. Collectively, we have provided evidence supporting that AHR is continuously undergoing CMA and activation of CMA suppresses the AHR function in A549 cells.

In order to determine therapeutic targeting of AhR in TNBC, we investigated the anti-cancer effects of the novel AhR ligand 11-chloro-7Hbenzimidazo[2,1-a]benzo[de]iso-quinolin-7-one (11-Cl-BBQ), which belongs to a class of high affinity, rapidly metabolized AhR ligands called benzimidazoisoquinolines (BBQs). 11-Cl-BBQ induced AhR-dependent cancer-cell selective growth inhibition and strongly inhibited colony formation in TNBC cells.

P1, N=78, Active, not recruiting, Bayer | Recruiting --> Active, not recruiting | N=143 --> 78 | Trial primary completion date: Apr 2025 --> Jan 2024

P1b, N=164, Recruiting, Bayer | N=78 --> 164 | Trial primary completion date: Jun 2025 --> Nov 2025

Three aryl-hydrocarbon receptor (AhR) selective inhibitors, BAY-2416964, GNF351 and CH-223191, were assayed alone and in combination with 25 approved or investigational anticancer agents in complex spheroids including tumor cells, endothelial cells, and mesenchymal stem cells...Combinations of AhR inhibitors with anticancer agents including doxorubicin, cisplatin, SN38, venetoclax, selinexor, and etoposide (https://dtp.cancer.gov/organization/dscb/obtaining/default.htm) produced primarily additive cytotoxicity in complex spheroids after a 7-day exposure...Bortezomib, a direct inhibitor of the chymotrypsin-like protease of the 26S proteasome, and pevonedistat, a NEDD8-activating enzyme inhibitor, produced additive or greater-than-additive cytotoxicity in some complex spheroids. However, the combination of BAY-2416964 with TAK-243, a ubiquitin activating enzyme inhibitor, produced profound greater-than-additive cytotoxicity in more than half of the 28 PDMR cell lines tested as complex spheroids...This project was funded in part with federal funds from the NCI, NIH, under contract no. HHSN261201500003I.

Here, we propose that a best-in-class AhR inhibitor, DA-4505, improves anti-tumor efficacy via modulation of tumor immune surveillance compared to BAY2416964, an AHR antagonist drug candidate being studied in the clinical phase. To evaluate anti-tumor effects of DA-4505 and BAY2416964, the two AhR inhibitors were dosed at 10 mg/kg once daily alone or in combination with aPD-1 (10 mg/kg) in surgical and chemotherapy models, and a PDX model (YHIM2004)...A tumor reduction was shown by treating DA-4505 alone or in combination with pembrolizumab compared to vehicle group (P<0.05)... The AhR inhibitor DA-4505 demonstrated an improvement in anti-tumor efficacy. In addition, it has shown a synergistic effect when combined with aPD-1. Discoveries from this study provide a preclinical rationale for future clinical implications in solid tumor.

P1, N=143, Recruiting, Bayer | Trial completion date: Jan 2024 --> Jun 2025 | Trial primary completion date: Nov 2023 --> Mar 2025