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Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
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Targeting SHP2 with an Active Site Inhibitor Blocks Signaling and Breast Cancer Cell Phenotypes

Dhanaji M Lade1, Yehenew M Agazie1

  • 1One Medical Center Drive, Department of Biochemistry and Molecular Medicine, School of Medicine, West Virginia University, P.O. Box 9142, Morgantown, West Virginia 26506, United States.

ACS Bio & Med Chem Au
|October 25, 2023
PubMed

Insights

A new compound, CNBCA, effectively targets the oncogenic Src homology phosphotyrosyl phosphatase 2 (SHP2) protein. This inhibitor shows improved potency and selectivity, suppressing breast cancer cell growth and phenotypes.

Area of Science:

  • Oncology
  • Biochemistry
  • Pharmacology

Background:

  • The Src homology phosphotyrosyl phosphatase 2 (SHP2) is an oncogenic protein implicated in cancer development.
  • Targeted therapies against SHP2 are crucial for treating various cancers, including breast cancer.
  • Previous development of an active site inhibitor, CNBDA, showed promise in suppressing breast cancer cell transformation phenotypes.

Purpose of the Study:

  • To improve the efficacy and potency of SHP2 inhibitors.
  • To evaluate a modified compound, CNBCA, derived from CNBDA.
  • To assess CNBCA's effectiveness in inhibiting SHP2 activity and its impact on breast cancer cell phenotypes.

Main Methods:

  • Chemical modification of CNBDA to produce CNBCA.
  • In vitro enzyme activity assays to determine potency and selectivity against SHP2, SHP1, and PTP1B.
  • Cellular assays to assess SHP2 inhibition, signaling pathway modulation, and effects on breast cancer cell proliferation, colony formation, and mammosphere growth.

Main Results:

  • CNBCA demonstrated a 5.7-fold increase in potency against SHP2 enzyme activity compared to the parent compound.
  • CNBCA exhibited enhanced selectivity for SHP2 over other protein tyrosine phosphatases (PTPs).
  • CNBCA effectively inhibited full-length SHP2 in cellular contexts, downregulated SHP2-mediated signaling, and suppressed key breast cancer cell phenotypes.

Conclusions:

  • CNBCA is a potent and selective inhibitor of SHP2.
  • Targeting SHP2 with CNBCA effectively suppresses breast cancer cell proliferation, colony formation, and mammosphere growth.
  • CNBCA represents a promising therapeutic strategy for targeting SHP2 in breast cancer treatment.

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