A research team led by Herbert Waldmann from the Max Planck Institute for Molecular Physiology in Dortmund and Georg Winter at the AITHYRA Institute in Vienna has developed a new class of compounds that target and destroy the enzyme IDO1, which is used by tumors to suppress immune responses. The study found that these molecules, called iDegs (IDO1 degraders), inhibit tumor growth in mice with SKOV-3 tumors and extend survival time.
The immune system typically protects against foreign substances, bacteria, viruses, and damaged cells through white blood cells known as T cells. Cytotoxic T cells are able to recognize cancer-specific structures on malignant cells and trigger their destruction. However, cancer cells have evolved mechanisms to evade detection or deactivate T cells by releasing certain signaling substances or metabolic products. They can also activate immune checkpoints on T-cells to slow down the immune response.
Modern immunotherapies use checkpoint inhibitors to release these 'brakes' on the immune system and are applied in treating various cancers such as melanoma, lung, colon, and breast cancer. These therapies benefit only some patients, and resistance often develops. Preclinical studies have shown that combining checkpoint inhibitors with blockers of the enzyme indoleamine 2,3 dioxygenase 1 (IDO1) can improve efficacy. IDO1 is abundant in many tumors but scarce in normal tissue; it converts tryptophan into kynurenine, which suppresses killer T cell activity.
To identify new IDO1 inhibitors, researchers developed a cell-based assay measuring tryptophan conversion to kynurenine and screened over 150,000 compounds. Several potent inhibitors were found with diverse mechanisms of action. Despite this progress, a large Phase 3 clinical trial showed no benefit from combining checkpoint inhibitors with conventional IDO inhibitors.
The failure of this trial may be due to the fact that even when inhibited, IDO1's presence alone could promote cancer growth. Researchers observed that many known IDO1 inhibitors actually increase levels of the protein. The newly identified iDegs overcome this issue by degrading IDO1 directly: binding induces a conformational change that marks the enzyme for destruction via ubiquitination—a process recognized by E3 ligase CRL2KLHDC3—which then leads it to proteasomal degradation.
Further studies confirmed that iDegs reduced tumor growth in mouse models and prolonged survival times.
Recent findings suggest potential applications for IDO1 modulation beyond cancer treatment; diseases associated with Epstein-Barr virus or Alzheimer's disease might also benefit from targeting this pathway. Interest remains high in developing IDO modulators: currently ten clinical studies involving IDO-1 are active worldwide with three more planned.
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