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Updated: May 23, 2025

Fully Processed Recombinant KRAS4b: Isolating and Characterizing the Farnesylated and Methylated Protein
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Discovery and Characterization of RP03707: A Highly Potent and Selective KRASG12D PROTAC

Xiang Ji1, Huanping Li1, Gang Wu1

  • 1Risen (Shanghai) Pharma Tech Co., Ltd., Shanghai 201210, China.

Journal of Medicinal Chemistry
|May 8, 2025
PubMed

Insights

Researchers developed RP03707, a novel Proteolysis Targeting Chimera (PROTAC), to degrade the KRASG12D oncoprotein. This targeted protein degradation approach shows significant promise for treating KRASG12D-mutant cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • KRASG12D mutations are common drivers in various cancers.
  • Targeting KRASG12D is crucial for effective cancer therapy.
  • Protein degradation offers a novel therapeutic strategy.

Purpose of the Study:

  • To investigate a Proteolysis Targeting Chimera (PROTAC) approach for KRASG12D.
  • To design and identify potent and selective KRASG12D degraders.
  • To evaluate the therapeutic potential of identified PROTACs in preclinical models.

Main Methods:

  • Rational design of KRASG12D-binding PROTACs.
  • Incorporation of a linker and E3 ligase ligand (CRBN).
  • In vitro cell line studies and in vivo CDX mouse models.

Main Results:

  • RP03707 identified as a potent and selective KRASG12D degrader.
  • RP03707 inhibited tumor cell growth in KRASG12D cell lines.
  • RP03707 demonstrated prolonged PK/PD effects and efficacy in mouse models.

Conclusions:

  • RP03707 is a promising therapeutic candidate for KRASG12D-driven tumors.
  • Targeted protein degradation via PROTACs is effective against KRASG12D mutations.
  • Further clinical investigation of RP03707 is warranted.

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