There has been considerable and promising development in the field of targeted protein degradation (TPD) since the seminal discovery of PROTACs in 2001.1 The appeal of degraders like PROTACs lies in their ability to resolve targets deemed “undruggable” by traditional inhibitor-based strategies.
We are now on the cusp of finally seeing TPD-based drugs in the clinic, as drug developers move to advance protein degraders within their pipelines. Arvinas LLC, for example, has two PROTAC® candidates that are now undergoing Phase 2 trials. One seeks to treat metastatic castration-resistant prostate cancer (mCRPC) by degrading the androgen receptor. Their other candidate aims to treat locally advanced or metastatic ER-positive/HER2-negative breast cancer by targeting the estrogen receptor. And, Kymera Therapeutics recently announced that their first PROTAC® to treat immuno-inflammatory diseases has entered a Phase 1 clinical trial. Their degrader candidate targets IRAK4, a key protein involved in inflammation mediated by the activation of TLRs and IL-1Rs.
A growing number of companies are also applying TPD strategies in other disease areas. Here are some examples of targeted diseases and where the protein degrader drug candidates stand in the company pipeline:
- Metastatic castration-resistant prostate cancer (mCRPC) – Phase 22
- ER+/HER2- breast cancer – Phase 22
- MYD88-mutant diffuse large B-cell lymphoma (DLBCL) – Preclinical3
- STAT3-driven cancers – Preclinical3
- Multiple myeloma & lymphoma – Preclinical5
- Synovial sarcoma & SMARCB1 deleted tumors – Preclinical5
- B-cell malignancies – Preclinical2
- KRAS-driven cancers – Preclinical2
- Drug-resistant BRAF mutant melanoma and NSCLC – Discovery5
- Drug-resistant RET-altered tumors – Discovery5
- Drug-resistant EGFR+ NSCLC – Discovery5
- Other unspecified cancers4,5,6,7
- Tau-driven neurodegeneration (FTLD-TAU, PSP, AD) – Preclinical2
- Alpha synuclein-driven neurodegeneration (MSA, Parkinson’s) – Discovery2
- mHTT-driven (Huntington’s) – Discovery2
- Other unspecified neurodegenerative diseases4
Inflammatory and autoimmune disease
- IL-1R/TLR pathway immune diseases – Phase 13
- Psoriasis and asthma – Preclinical4
- Cystic Fibrosis – Discovery4
In the coming months, we can expect to see more exciting breakthroughs in TPD in both the academic and clinical sectors. Learn how NanoTemper tools can help drive PROTAC technology from discovery to clinical development.