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

Yuan Fang1, Shuhang Wang1, Songzhe Han2

  • 1Clinical Trials Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.

Trends in Pharmacological Sciences
|April 14, 2023
PubMed

Insights

Targeted protein degradation (TPD) offers new ways to treat cancer by targeting previously undruggable proteins. This review examines TPD clinical trials and discusses challenges for future drug development.

Area of Science:

  • Oncology
  • Pharmacology
  • Biochemistry

Background:

  • Traditional anticancer therapies target kinases, but many cancer proteins lack catalytic activity, limiting drug development.
  • Targeted protein degradation (TPD) emerges as a novel therapeutic strategy to address these challenging targets.
  • The field of TPD has rapidly advanced with new-generation drugs like IMiDs, SERDs, and PROTACs entering clinical trials.

Purpose of the Study:

  • To provide an overview of the global clinical trial landscape for TPD drugs over the last decade.
  • To summarize the clinical profiles of emerging TPD therapeutics.
  • To identify key challenges and opportunities for advancing TPD drug development and clinical translation.

Main Methods:

  • Systematic review of clinical trials involving targeted protein degradation drugs.
  • Analysis of clinical data and profiles of new-generation TPD agents.
  • Literature synthesis on challenges and future directions in TPD research.

Main Results:

  • Explosive growth in TPD clinical trials over the past 10 years.
  • Successful entry of novel TPD modalities (IMiDs, SERDs, PROTACs) into clinical development.
  • Identification of persistent challenges hindering widespread clinical translation of TPD drugs.

Conclusions:

  • TPD has significantly expanded the druggable proteome for cancer therapy.
  • Further research is needed to overcome existing challenges for successful clinical translation of TPD drugs.
  • Opportunities exist for developing more effective TPD therapies to improve cancer treatment outcomes.
Keywords:
IMiDPROTACSERDcancerprotein degradation

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