Protein degraders show promising results in drug development pipelines. See progress candidates have made.

April 21, 2021 Patricia Piatti

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:

Cancer/Oncology:

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 – Clinical⁵
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 – Preclinical⁵
Other unspecified cancers^4,5,6,7

Neurodegenerative

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

Genetic Disorders

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.

Sources:

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Protein degraders show promising results in drug development pipelines. See progress candidates have made.

Cancer/Oncology:

Neurodegenerative

Inflammatory and autoimmune disease

Genetic Disorders

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