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Updated: May 31, 2025

From a 2DE-Gel Spot to Protein Function: Lesson Learned From HS1 in Chronic Lymphocytic Leukemia
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Targeting Protein-Protein Interactions in Hematologic Malignancies

Tomasz Cierpicki1, Jolanta Grembecka1

  • 1Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA; email: tomaszc@umich.edu, jolantag@umich.edu.

Annual Review of Pathology
|January 24, 2025
PubMed

Insights

Small-molecule inhibitors targeting protein-protein interactions (PPIs) show significant promise for treating blood cancers. Recent clinical successes, including FDA-approved venetoclax, highlight the therapeutic potential of blocking these critical cancer-driving interactions.

Area of Science:

  • Oncology
  • Medicinal Chemistry
  • Pharmacology

Background:

  • Protein-protein interactions (PPIs) are crucial in cancer development, making them attractive therapeutic targets.
  • Developing small-molecule inhibitors for PPIs presents unique challenges but offers novel treatment strategies for malignancies.
  • Hematologic malignancies represent a key area where PPI inhibitors are being actively investigated.

Purpose of the Study:

  • To review successful protein-protein interaction (PPI) inhibitors that have advanced to clinical studies in hematologic malignancies.
  • To discuss the challenges and lessons learned in developing small-molecule PPI inhibitors for cancer therapy.
  • To highlight the clinical value and therapeutic promise of targeting PPIs in hematologic cancers.

Main Methods:

  • Review of clinical trial data and scientific literature on small-molecule protein-protein interaction (PPI) inhibitors.
  • Analysis of the development pathways and clinical outcomes of approved and investigational PPI inhibitors.
  • Discussion of resistance mechanisms and strategies for overcoming them in the context of hematologic malignancies.

Main Results:

  • Several protein-protein interaction (PPI) inhibitors have progressed to clinical studies for hematologic malignancies.
  • The FDA approval of venetoclax validates the clinical efficacy of targeting protein-protein interfaces.
  • Successful development requires overcoming significant challenges in drug design, delivery, and resistance.

Conclusions:

  • Small-molecule inhibitors targeting protein-protein interactions (PPIs) represent a successful and promising therapeutic strategy for hematologic malignancies.
  • Continued research and development in PPI inhibition are crucial for advancing cancer treatment.
  • Lessons learned from clinical studies are vital for optimizing future PPI inhibitor development.
Keywords:
drug discoveryhematologic malignanciesprotein–protein interactionstargeted therapies

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