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Updated: May 23, 2025

A Customizable Approach for the Enzymatic Production and Purification of Diterpenoid Natural Products
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Ingenane Diterpenoids from Euphorbia peplus as Potential New CHK1 Inhibitors That Sensitize Cancer Cells to

Mi Zhou1,2, Yanlan Yang1, Shoulun He1

  • 1School of Pharmaceutical Science, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen 361002, China.

Journal of Natural Products
|March 8, 2025
PubMed

Insights

Two new compounds from Euphorbia peplus inhibit p-CHK1(S345), a key factor in chemotherapy resistance. Compound 8 enhances cancer drug efficacy by blocking this target, offering a novel therapeutic strategy.

Area of Science:

  • Natural Products Chemistry
  • Cancer Biology
  • Pharmacology

Background:

  • Phosphorylation of checkpoint kinase 1 (p-CHK1(S345)) is crucial for the replication stress response in cancer, contributing to chemotherapy resistance.
  • Developing inhibitors of p-CHK1(S345) is a key strategy to overcome acquired drug resistance in cancer therapy.

Purpose of the Study:

  • To identify and characterize novel inhibitors of p-CHK1(S345) from Euphorbia peplus.
  • To investigate the structure-activity relationship (SAR) of ingenane diterpenoids against p-CHK1(S345).
  • To explore the potential of identified compounds in enhancing cancer chemotherapy sensitivity.

Main Methods:

  • Isolation and structural elucidation of 14 ingenane diterpenoids from Euphorbia peplus, including two novel compounds.
  • In vitro screening of isolated compounds for inhibitory effects on p-CHK1(S345).
  • In vivo evaluation of compound 8 in combination with topotecan.
  • Mechanistic studies involving CHK1 ubiquitination and protein kinase C (PKC) activation.

Main Results:

  • Two undescribed ingenane diterpenoids with an exocyclic double bond were identified.
  • Compounds 7 and 8 exhibited potent inhibition of p-CHK1(S345), abrogated cell cycle arrest, and increased DNA damage.
  • Compound 8 enhanced the anticancer efficacy of topotecan in vivo by blocking p-CHK1(S345).
  • Compound 8 promotes CHK1 ubiquitination and inhibits p-CHK1(S345) through PKC activation.

Conclusions:

  • Compound 8 demonstrates potential as a novel CHK1 inhibitor for cancer therapy.
  • PKC activation plays a previously unrecognized role in enhancing cancer chemotherapy sensitivity by regulating CHK1 ubiquitination.
  • This study provides a new therapeutic avenue targeting the p-CHK1(S345) pathway and PKC signaling.

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