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Updated: Sep 10, 2025
07:08
Fully Processed Recombinant KRAS4b: Isolating and Characterizing the Farnesylated and Methylated Protein
Published on: January 16, 2020
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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
Summary
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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