Watertown Bio Journal Club: How Targeted is Targeted Protein Degradation?
Welcome to the first Journal Club of 2026! Watertown Bio Journal Club is a monthly publication highlighting the scientific research produced by labs in Watertown. If you’re a Watertown-based biotech and have a recently published article, pre-print, or conference publication you would like featured in our next issue, reach out at newsletter@watertown.bio. If you enjoy our publications consider supporting us.
Featured Article: Developmental toxicology profile of the IRAK4 degrader KT-474
Our featured article, published in Toxicological Sciences by Kymera Therapeutics investigating the developmental toxicity of their heterobifunctional degrader (PROTAC) KT-474 targeting IRAK4 for the treatment of hidradenitis suppurativa and atopic dermatitis (eczema). PROTACs are small molecules that recruit an E3 ligase to activate the ubiquitin-proteosome pathway and selectively degrade the targeted protein. There are different E3 ligases, but one common E3 ligase is CRBN, which is used in KT-474.
Potential safety concerns arise with CRBN-based PROTACs because the CRBN recruitment domain in many PROTACs share some structural similarities to immunomodulatory imide drugs (IMiDs) like pomalidomide or thalidomide. In the 1960’s, thalidomide was prescribed around the world to treat morning sickness, but the drug caused severe birth defects in children as well as an increased rate in miscarriages. The US was mainly spared from the tragedy because FDA reviewer Dr. Frances Oldham Kelsey was concerned by the lack of safety data. Despite pressure from the applicant, she refused to approve the drug without clearer data. Ultimately, thalidomide was recalled in Europe after reports of birth defects, Dr. Kelsey was given an award by President Kennedy for preventing a thalidomide tragedy in the US, and Congress reformed the FDA to strengthen review of new drugs.
In the 1990’s, IMiDs like thalidomide have found a role in oncology and have been FDA approved to treat cancers like multiple myeloma. Continued research into IMiD mechanism of action suggests that they work by recruiting CRBN to degrade a number of proteins, including some that are responsible for development. Since KT-474 uses an E3 ligase recruitment domain derived from the IMiD pomalidomide, Kymera initiated this study to evaluate and address potential off-target degradation of developmental proteins by their PROTAC.
The authors started with in-vitro studies that used mass spectrometery to measure protein degradation in cells treated with KT-474 or pomalidomide , with a special focus on a panel of 21 previously reported development-associated proteins degraded by IMiDs in vitro or in rabbit embryos. The authors found that across 3 different cell lines, KT-474 selectively degraded it target IRAK4, but none of the panel of development proteins. In contrast, Pomalidomide significantly degraded 10 of the 21 panel proteins. Similarly, no fetal malformations or embryo-fetal toxicity were observed in mouse or rabbit models across a variety of doses, includes doses higher than the human equivalent used in KT-474’s Phase 1 and 2 clinical trials. Together, the data suggest that the CRBN recruitment domain in KT-474 doesn’t exhibit the same off-target degradation of developmental proteins characteristic of IMiDs. While this study produced positive results, Kymera and their partner Sanofi ultimately chose not to continue developing KT-474, instead choosing to focus on their second generation IRAK4 degrader, KT-485.
In the big picture, these kinds of studies serve as an example of the review required of new kinds of drugs. It’s why Arvinas’ PROTAC review by the FDA is something Watertown Bio is watching in 2026: as the first PROTAC to under go FDA review, it lays out a guide for what safety and efficacy data the FDA expects for this new class of drugs, which could potentially have a large impact on Watertown’s burgeoning targeted protein degradation cluster.
If you enjoyed Journal Club please share!
