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Identification of a p21-activated kinase 1 (PAK1) inhibitor with 10-fold selectivity against PAK2

Deidre M Johns1, Jason Olejniczak1, Anjali Babbar1

  • 1Turning Point Therapeutics, Inc. (a wholly owned subsidiary of Bristol Myers Squibb Company), 10628 Science Center Drive, Suite 200, San Diego, CA 92121, United States.

Bioorganic & Medicinal Chemistry Letters
|June 14, 2025
PubMed

Insights

Researchers developed a novel small molecule inhibitor targeting p21-activated kinase 1 (PAK1), crucial in cancer. This inhibitor shows tenfold selectivity for PAK1 over PAK2, a related protein linked to cardiotoxicity.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Drug Discovery

Background:

  • p21-activated kinases (PAKs) regulate cytoskeleton, cell shape, and survival.
  • PAK1 is implicated in tumorigenesis and amplified in breast, ovarian, and melanoma cancers.
  • PAK2, though structurally similar to PAK1, is associated with cardiotoxicity.

Purpose of the Study:

  • To design a small molecule inhibitor with selectivity for PAK1 over PAK2.
  • To leverage structural information for targeted drug development against PAK1.

Main Methods:

  • Determined the first crystal structure of PAK2.
  • Employed structure-based drug design principles.
  • Synthesized and tested small molecule inhibitors for PAK1/PAK2 selectivity.

Main Results:

  • Reported the first crystal structure of PAK2.
  • Designed and identified a novel small molecule inhibitor.
  • Achieved tenfold selectivity for PAK1 inhibition over PAK2.

Conclusions:

  • The first PAK2 crystal structure enables structure-based design of PAK1-selective inhibitors.
  • This selective inhibitor represents a promising therapeutic strategy for PAK1-driven cancers.
  • Targeting PAK1 while sparing PAK2 may mitigate cardiotoxicity concerns.
Keywords:
KinaseMedicinal chemistryOncologyPAKStructure-based drug discoverycancer

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