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Structure-activity relationships of KRAS-G12D inhibitors for pancreatic cancer

Chetna Suyal1, K Mangala Shenoy1, Anoop Kishore2

  • 1Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education (MAHE), Manipal, Karnataka 576104, India.

Drug Discovery Today
|June 10, 2025
PubMed

Insights

Researchers are exploring small molecules to inhibit the KRASG12D mutation, a common driver in pancreatic cancer. This review details structure-activity relationship studies for potential KRAS-G12D targeted therapies against pancreatic ductal adenocarcinoma.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • KRAS (Kirsten rat sarcoma viral oncogene homolog) is a GTPase vital for cellular signaling, proliferation, and survival.
  • KRAS mutations are implicated in numerous cancers, particularly pancreatic ductal adenocarcinoma (PDAC), occurring in ~95% of cases.
  • Targeting KRAS mutations remains a significant challenge in cancer therapy, with no approved drugs for the prevalent KRASG12D mutation in PDAC.

Purpose of the Study:

  • To review structure-activity relationship (SAR) studies of small organic molecules targeting the KRAS-G12D mutation.
  • To highlight ongoing research and potential therapeutic strategies for KRAS-G12D-driven pancreatic cancer.

Main Methods:

  • Literature review of SAR studies focused on KRAS-G12D inhibitors.
  • Analysis of small organic molecules investigated for their efficacy against KRAS-G12D.

Main Results:

  • Identification of various small molecules demonstrating inhibitory activity against KRAS-G12D.
  • Detailed SAR insights guiding the design of more potent and selective KRAS-G12D inhibitors.

Conclusions:

  • Small molecule inhibitors targeting KRAS-G12D show promise for treating pancreatic cancer.
  • Continued SAR studies are crucial for developing effective therapies against KRAS-mutated PDAC.
Keywords:
KRASKRAS-G12Dmutationspancreatic cancerscaffoldsstructure–activity relationship

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