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Challenges for drug discovery - a case study of urokinase receptor inhibition

Zhuo Chen1, Lin Lin, Qing Huai

  • 1State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, China.

Combinatorial Chemistry & High Throughput Screening
|December 23, 2009
PubMed

Insights

Developing urokinase receptor (uPAR) inhibitors for cancer treatment faces challenges like poor bioavailability and specificity. Structural insights are crucial for advancing uPAR inhibitor drug discovery.

Area of Science:

  • Biochemistry
  • Drug Discovery
  • Structural Biology

Background:

  • Urokinase receptor (uPAR) is a validated target for cancer therapy.
  • Over a decade of research has yielded potent uPAR inhibitors, yet none have advanced in the drug discovery pipeline.

Purpose of the Study:

  • To elucidate the challenges in developing uPAR inhibitors.
  • To highlight the role of structural information in overcoming these challenges and advancing drug discovery.

Main Methods:

  • Analysis of existing uPAR inhibitor development strategies.
  • Review of recently determined crystal structures of uPAR in complex with ligands or inhibitors.

Main Results:

  • Identified key challenges: hydrophobicity leading to poor bioavailability, specificity issues with peptidyl inhibitors causing conformational changes, and species specificity hindering preclinical validation.
  • Structural data provides insights into these challenges and potential solutions for inhibitor design.

Conclusions:

  • Structural information is critical for understanding and overcoming hurdles in uPAR inhibitor development.
  • Further inhibitor development can be facilitated by leveraging structural insights for improved drug design and preclinical validation.

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