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Synthetic Optimization and MAPK Pathway Activation Anticancer Mechanism of Polyisoprenylated Cysteinyl Amide

Nada Tawfeeq1, Yonghao Jin1, Nazarius S Lamango1

  • 1College of Pharmacy and Pharmaceutical Sciences, Institute of Public Health, Florida A&M University, Tallahassee, FL 32307, USA.

Cancers
|November 27, 2021
PubMed

Insights

Polyisoprenylated cysteinyl amide inhibitors (PCAIs) show promise as targeted cancer therapies by effectively suppressing KRAS-mutant cancer cell viability. These PCAIs impact the RAS-MAPK signaling pathway, suggesting potential for treating cancers with aberrant G-protein signaling.

Area of Science:

  • Oncology
  • Molecular Biology
  • Medicinal Chemistry

Background:

  • Aberrant signaling in the MAPK pathway, particularly mutations in RAS GTPases (found in 30% of cancers), drives cancer initiation and progression.
  • Targeted therapies are needed for RAS-driven cancers, highlighting the importance of understanding pathway mediators.

Purpose of the Study:

  • To optimize Polyisoprenylated cysteinyl amide inhibitors (PCAIs) as potential targeted therapies for RAS-driven cancers.
  • To elucidate the mechanisms of action of PCAIs in KRAS-mutant cancer cells.

Main Methods:

  • Optimization of PCAIs, assessing their physicochemical properties (ClogP values).
  • Evaluation of PCAI efficacy in suppressing cell viability of KRAS-mutant cell lines (MDA-MB-231, A549, MIA PaCa-2, NCI-H1299) in 2D and 3D cultures.
  • Analysis of the impact of PCAIs on key proteins within the RAS-MAPK signaling pathway (Raf, MEK1/2, ERK1/2, p90RSK) using Western blotting.

Main Results:

  • PCAIs demonstrated significant suppression of viability in multiple KRAS-mutant cancer cell lines with low micromolar EC50 values.
  • Treatment with a specific PCAI (NSL-YHJ-2-27) stimulated the phosphorylation of MEK1/2, ERK1/2, and p90RSK, indicating pathway activation.
  • A non-farnesylated analog (NSL-YHJ-2-62) did not produce similar signaling effects, suggesting the importance of farnesylation for PCAI activity.

Conclusions:

  • The anticancer effects of PCAIs are likely mediated through modulation of the RAS-MAPK signaling axis, potentially involving proapoptotic isoforms of p90RSK.
  • PCAIs represent a promising therapeutic strategy for cancers characterized by aberrant hyperactive G-protein signaling, addressing unmet clinical needs.
Keywords:
ERK1/2KRASMAPKMEK1/2PCAIsp90RSK

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