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Updated: Sep 10, 2025

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Discovery of KRAS(G12D) selective degrader ASP3082

Tomohiro Yoshinari1, Takeyuki Nagashima2, Hiroki Ishioka2

  • 1Engineered Small Molecules, Astellas Pharma Inc., Tsukuba, Japan. tomohiro.yoshinari@astellas.com.

Communications Chemistry
|August 23, 2025
PubMed

Insights

Researchers developed ASP3082, a novel degrader targeting the common KRAS(G12D) mutation in cancer. This compound effectively degrades the KRAS(G12D) protein, showing promise for treating KRAS(G12D)-mutated cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Kirsten rat sarcoma viral oncogene homolog (KRAS) is a frequently mutated oncogene in various cancers.
  • KRAS(G12D) is the most common KRAS mutation, yet lacks approved targeted therapies, unlike KRAS(G12C).

Purpose of the Study:

  • To discover and characterize ASP3082, a selective degrader targeting the KRAS(G12D) mutation.
  • To demonstrate a structure-based optimization approach for bifunctional proximity-inducing drugs.

Main Methods:

  • Discovery and characterization of ASP3082, a KRAS(G12D)-selective degrader.
  • Determination of the crystal structure of the KRAS(G12D)/ASP3082/VHL ternary complex.
  • Evaluation of ASP3082's efficacy in KRAS(G12D)-mutated cancer xenograft models.

Main Results:

  • ASP3082 selectively induces degradation of KRAS(G12D) protein.
  • The drug exhibits potent and durable pharmacological activity.
  • ASP3082 treatment led to significant tumor regression in preclinical cancer models.

Conclusions:

  • ASP3082 is a promising therapeutic candidate for KRAS(G12D)-mutated cancers.
  • The structure-based optimization strategy can be applied to other proximity-inducing drugs.
  • ASP3082 is currently under clinical investigation.

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