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Updated: Jul 13, 2025

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Structure-Based Design and Synthesis of Potent and Selective KRAS G12D Inhibitors

Hengmiao Cheng1, Puhui Li1, Ping Chen1

  • 1Erasca Inc., 3115 Merryfield Row, Suite 300, San Diego, California 92121, United States.

ACS Medicinal Chemistry Letters
|October 18, 2023
PubMed

Insights

Researchers developed a new drug, ERAS-5024, targeting the KRAS G12D mutation common in pancreatic cancer. This potent inhibitor shows promise in preclinical studies, reducing tumor growth and proliferation.

Area of Science:

  • Oncology
  • Medicinal Chemistry
  • Molecular Biology

Background:

  • The KRAS G12D mutation is prevalent in pancreatic ductal adenocarcinoma (PDAC), representing a significant therapeutic target.
  • Targeting oncogenic KRAS mutations is a critical area of cancer research.

Purpose of the Study:

  • To design and synthesize novel, potent, and selective inhibitors targeting the KRAS G12D mutation.
  • To evaluate the preclinical efficacy of the lead compound ERAS-5024 in relevant cancer models.

Main Methods:

  • Structure-based drug design principles were employed to identify potential inhibitors.
  • In vitro assays (e.g., Cell-Titer Glo) were used to assess compound potency and effects on cell proliferation.
  • In vivo efficacy studies were conducted to evaluate tumor regression.

Main Results:

  • A series of potent and selective KRAS G12D inhibitors were successfully designed and synthesized.
  • The lead compound, ERAS-5024, demonstrated single-digit nanomolar potency in inhibiting ERK1/2 phosphorylation and cell proliferation in AsPC-1 PDAC cells.
  • ERAS-5024 exhibited significant tumor regression in in vivo efficacy studies.

Conclusions:

  • The discovery of ERAS-5024 represents a significant advancement in targeting KRAS G12D-mutated pancreatic cancer.
  • ERAS-5024 shows potential as a therapeutic agent for PDAC and warrants further clinical investigation.

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