xirestomig (ATG-101)

Previously, we developed small molecule ULK1 inhibitors that not only inhibit ULK kinase activity but also induced the degradation of other core members of the ULK complex including ATG101 and ATG13...Finally, immunohistochemical staining of orthotopic pancreatic tumors reveals a significant increase in CD4⁺ and CD8⁺ T cell infiltration upon treatment, suggesting that SBP-1750 enhances anti-tumor immunity. These findings support further development of SBP-1750 as a novel ATG-targeting cancer therapy.

P1, N=33, Terminated, Antengene (Hangzhou) Biologics Co., Ltd. | Active, not recruiting --> Terminated | Trial primary completion date: Aug 2025 --> Mar 2025 | N=62 --> 33 | Trial completion date: Dec 2025 --> Mar 2025; The sponsor has decided to adjust the development strategy of the investigational drug in this study.

P1, N=31, Terminated, Antengene Biologics Limited | Trial completion date: Jan 2026 --> Jan 2025 | Recruiting --> Terminated | Trial primary completion date: Oct 2025 --> Jan 2025; It is due to the recent changes in the competitor landscape and strategic consideration

Mechanism research revealed that AZ-9 recruits ATG101 to initiate the autophagy-lysosome pathway, and forms autophagosomes through the recruitment of LC3, which then fuses with lysosomes to degrade CDK9 and the partner protein Cyclin T1. These dates validated the existence of non-proteasomal degradation pathway of hydrophobic driven protein degradation strategy for the first time, which might provide research ideas for chemical induction intervention on other types of pathogenic proteins.

P1, N=62, Active, not recruiting, Antengene (Hangzhou) Biologics Co., Ltd. | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Aug 2024 --> Aug 2025 | Recruiting --> Active, not recruiting

Virtualization of the interaction of Lf protein with ATG101, mTOR and AMPK proteins by Pymol software showed that the N lobe region of Lf interacted with the HORMA domain of ATG101 protein, the fat domain of mTOR protein, and the CTD domain of AMPK protein. Although Lf was not able to increase the expression of autophagy-inducing genes, it may be able to induce autophagy through protein interaction by activating or inhibiting proteins related to autophagy regulation.

[89Zr]Zr-Df-ATG-101 in vivo distribution is dependent on PD-L1 expression in the MDA-MB-231 xenograft model. Immuno-PET with [89Zr]Zr-Df-ATG-101 provides real-time information about ATG-101 distribution and tumour uptake in vivo. Our data support the use of [89Zr]Zr-Df-ATG-101 to assess tumour and tissue uptake of ATG-101.

P1, N=40, Recruiting, Antengene Biologics Limited | N=482 --> 40

As a co-expressed gene (CEG), ATG101 was up-regulated in CC tissues and indicated poor survival. ULK1 is closely related to immune cells. ULK1 expression is upregulated in CC cells and upregulation of ULK1 may serve as an accurate prognostic factor, thereby providing novel intervention targets for therapy.

Furthermore, the PTCH1 CTD mutant cells displayed increased proliferation in the presence of rapamycin and reduced sensitivity to glycolysis inhibitors. Our findings suggest that loss of the PTCH1-ATG101 interaction by mutations in the CTD of PTCH1 in cancer might confer a selective advantage by stimulating autophagy and facilitating adaptation to nutrient deprivation conditions.

The ATS signature predicts the drug resistance to the immunotherapy, thus a combination of targeted therapy and immunotherapy might be suitable for ATS-high patients. This work shed light on the function of ATG101-related genes in HCC and revealed that the ATS signature may be a useful prognostic biomarker for differentiating molecular and immunological features and predicting probable response to the therapy.