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Strategic Design and Development of Indole-Based Compounds as Potent Malic Enzyme 3 Inhibitors for Pancreatic Tumor

Gaurav Sheth1,2, Shailesh R Shah2, Prabal Sengupta1,3

  • 1Department of Medicinal Chemistry, Sun Pharma Advanced Research Company Ltd., Vadodara, 391775, India.

Chemmedchem
|September 14, 2025
PubMed

Insights

Targeting malic enzyme 3 (ME3) offers a new strategy for pancreatic cancer. Researchers developed novel ME3 inhibitors, with compound 13 showing promise, especially when combined with MEK inhibitors.

Area of Science:

  • Biochemistry
  • Oncology
  • Medicinal Chemistry

Background:

  • Malic enzyme 3 (ME3) is crucial for the survival of SMAD4/ME2-deficient pancreatic ductal adenocarcinoma (PDAC) cells.
  • ME3 supports cancer cell energy production and redox balance, making it a potential therapeutic target.

Purpose of the Study:

  • To identify novel chemotypes targeting ME3 through systematic structure-activity relationship (SAR) studies.
  • To discover potent ME3 inhibitors for treating PDAC with specific genetic deletions.

Main Methods:

  • Systematic SAR exploration of ME3 inhibitors.
  • Synthesis and evaluation of indole-substituted piperazine carboxamides.
  • Assessment of compound 13 efficacy in PDAC cell lines.
  • Evaluation of synergistic effects with MEK inhibitor trametinib.

Main Results:

  • Discovery of a new series of potent ME3 inhibitors, including indole-substituted piperazine carboxamides.
  • Compound 13 demonstrated significant ME3 inhibitory activity in PDAC cell lines.
  • Compound 13 exhibited synergistic effects with trametinib in Hs766T cells.

Conclusions:

  • Targeting ME3 is a viable therapeutic strategy for SMAD4/ME2-deleted PDAC.
  • Compound 13 represents a promising lead compound for PDAC treatment.
  • Combination therapy with ME3 and MEK inhibitors may enhance treatment efficacy.
Keywords:
ME3 inhibitorsPDACanticancer agentscollateral lethalitymalic enzymes

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