UCLA researchers from the Department of Chemistry and Biochemistry have developed a novel chemical modification of PROTACs to increase their selectivity under hypoxic conditions.
BACKGROUND: Proteolysis targeting chimeras (PROTACs) are molecules that induce targeted degradation of proteins by recruiting a ubiquitin ligase to a protein of interest (POI). PROTACs have been used as novel treatments to target previously “undruggable” disease-causing proteins since they can directly bind to the protein without needing to inhibit its active site. However, off-target toxicities have limited their therapeutic window due to effects in healthy tissues. To overcome this issue, researchers have tried to enable context-specific release of PROTACs, particularly in the context of cancer, since tumors can be hypoxic (low oxygen). While promising, these approaches remain under development. Therefore, there is a demand for innovative strategies that enable precise, context-specific PROTAC activation, especially in the context of hypoxia.
INNOVATION: Researchers at UCLA have introduced a novel approach which involves chemical modification of PROTACs to increase their selectivity in hypoxic conditions such as tumor microenvironments. UCLA researchers generated chemically modified PROTACs, termed hypoxia-activated PROTACs (HAP-TACs), and validated through enzyme-based assays that the HAP-TACs were only active in hypoxic conditions. The HAP-TACs were then evaluated for their ability to induce the degradation of a protein of interest in cells under hypoxic and normoxic conditions. These HAP-TACs demonstrated selective activation in hypoxic conditions. Lastly, UCLA researchers investigated the anti-proliferative effects of the HAP-TACs and found that they did not affect cell growth in normoxia, but effectively reduced cell number in hypoxia. In summary, UCLA researchers have developed HAP-TACs that can degrade target proteins under hypoxic conditions. This finding provides potential for novel tissue-specific therapeutics.
POTENTIAL APPLICATIONS:
- Treatment of cancer
- Treatment of neurodegenerative diseases
ADVANTAGES:
- Increased tissue specificity compared to other PROTACs
- Low off-target protein effects compared to other PROTACs
DEVELOPMENT-TO-DATE: UCLA researchers have chemically modified PROTACs into HAP-TACs and tested their function through both in vitro enzyme-based assays and in-cell screening. They have shown that the HAP-TACs can degrade target proteins in hypoxic conditions, exhibiting little effects in normoxic environments.
Keywords: PROTACs, hypoxia, ubiquitin ligase, active site, HAP-TACs, tumor microenvironment, enzyme-based assay, normoxia