Targeted protein degrader development for cancer: advances, challenges, and opportunities.

We overview global clinical trials of targeted protein degradation (TPD) drugs for oncology across the past decade. The most common classes of TPD drugs in oncology clinical trials are selective estrogen receptor degraders (SERDs), immunomodulatory drugs (ImiDs), and proteolysis-targeting chimeras (PROTACs), all of which target protein degradation via the ubiquitin–proteasome system. Second-generation IMiDs with improved degradation potency could overcome resistance to lenalidomide and can treat more types of hematologic malignancies. The clinical development of oral SERDs still has many challenges, but several drugs have recently shown promising results in breast cancer patients with ESR1 mutations. Oral bioavailability and pharmacokinetics are two main issues that need to be addressed when developing clinically applicable PROTACs. Anticancer-targeted therapies inhibit various kinases implicated in cancer and have been used in clinical settings for decades. However, many cancer-related targets are proteins without catalytic activity and are difficult to target using traditional occupancy-driven inhibitors. Targeted protein degradation (TPD) is an emerging therapeutic modality that has expanded the druggable proteome for cancer treatment. With the entry of new-generation immunomodulatory drugs (IMiDs), selective estrogen receptor degraders (SERDs), and proteolysis-targeting chimera (PROTAC) drugs into clinical trials, the field of TPD has seen explosive growth in the past 10 years. Several challenges remain that need to be tackled to increase successful clinical translation of TPD drugs. We present an overview of the global landscape of clinical trials of TPD drugs over the past decade and summarize the clinical profiles of new-generation TPD drugs. In addition, we highlight the challenges and opportunities for the development of effective TPD drugs for future successful clinical translation. [ABSTRACT FROM AUTHOR]