P1/2, N=125, Recruiting, Dong-A ST Co., Ltd. | Not yet recruiting --> Recruiting | Trial completion date: Apr 2030 --> Oct 2029

Our study reveals comparatively better chemistry of PALB2-resveratrol than PALB2-olaparib. Considering the current surge in the discovery of precision medicine in biomarker-based cancer therapeutics, this study proposes PALB2-resveratrol as a unique drug-receptor combination thus awaiting validation through in vitro studies.

P1, N=0, Withdrawn, Ikena Oncology | Phase classification: P1b --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 Withdrawn | Trial primary completion date: Jul 2024 --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=78, Completed, Ikena Oncology | Recruiting --> Completed | Trial completion date: Sep 2022 --> Jul 2023 | Trial primary completion date: Sep 2022 --> Jul 2023

P1/2, N=125, Not yet recruiting, Dong-A ST Co., Ltd.

PHGDH knockdown induced CRC cell sensitivity to stemregenin 1 via the autophagy pathway. Our findings suggest that PHGDH modulates AhR signaling and the redox-dependent autophagy pathway in CRC, and that the combination of inhibition of both PHGDH and AhR may be a novel therapeutic strategy for CRC.

The results indicate that correction of aberrant tryptophan catabolism in fibroids could be an effective treatment through its effect to reduce cell proliferation and ECM accumulation.

The aryl hydrocarbon receptor (AhR) antagonist CH223191 promoted, whereas the p38 inhibitor SB203580 suppressed the increase in TNFα mRNA and protein expression induced by skatole in intestinal epithelial Caco-2 cells. The c-Jun N-terminal kinase (JNK) inhibitor SP600125 repressed only the increased TNFα protein expression, whereas the extracellular signal-regulated kinase (ERK) pathway inhibitor U0126 did not affect increased TNFα expression at any level...Overall, these results suggested that TNFα expression is increased by the concerted actions of skatole-activated p38 and JNK, and that TNFα exerts autocrine/paracrine actions on IECs despite partial suppression by activated AhR. Therefore, skatole might play an important role in the development and progression of IBD and CRC via increased TNFα expression.

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.

Additionally, the AHR inhibitor (CH-223191) abrogated AHR activity and subsequent luminescence below control threshold...Future experiments will focus on using our reporter construct in the context of ICB treatment and assessing AHR activity overtime as well as sampling peripheral blood to assess the magnitude of tryptophan, kyn, and other polycyclic hydrocarbons including gut microbiome-derived indoles. The characterization of the IDO-Kyn-AhR modulation after therapeutic intervention will inform the rational design of treatment regimens to abrogate immune suppression associated with AHR activity in combination with ICB treatment.

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

The pharmacological inhibition of AhR, by CH223191, suppressed cell death signs and increased cell viability...Fascinatingly, during CCoV infection, a novel co-expression of NP and AhR expression was found. Taken together, our preliminary findings show that infection with CCoV activates AhR, and pharmacologic AhR inhibition reduces CCoV replication, identifying AhR as a possible candidate target for CCoV antiviral therapy.