Development of PROTACS degrading KRAS and SOS1
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Gerhard Hamilton1, Marie-Therese Eggerstorfer1, Sandra Stickler1
1Institute of Pharmacology, Medical University of Vienna, Vienna, 1090, Austria.
Abstract:
The Kirsten rat sarcoma virus-son of sevenless 1 (KRAS-SOS1) axis drives tumor growth preferentially in pancreatic, colon, and lung cancer. Now, KRAS G12C mutated tumors can be successfully treated with inhibitors that covalently block the cysteine of the switch II binding pocket of KRAS. However, the range of other KRAS mutations is not amenable to treatment and the G12C-directed agents Sotorasib and Adragrasib show a response rate of only approximately 40%, lasting for a mean period of 8 months. One approach to increase the efficacy of inhibitors is their inclusion into proteolysis-targeting chimeras (PROTACs), which degrade the proteins of interest and exhibit much higher antitumor activity through multiple cycles of activity. Accordingly, PROTACs have been developed based on KRAS- or SOS1-directed inhibitors coupled to either von Hippel-Lindau (VHL) or Cereblon (CRBN) ligands that invoke the proteasomal degradation. Several of these PROTACs show increased activity in vitro and in vivo compared to their cognate inhibitors but their toxicity in normal tissues is not clear. The CRBN PROTACs containing thalidomide derivatives cannot be tested in experimental animals. Resistance to such PROTACS arises through downregulation or inactivation of CRBN or factors of the functional VHL E3 ubiquitin ligase. Although highly active KRAS and SOS1 PROTACs have been formulated their clinical application remains difficult.
Insights
New proteolysis-targeting chimeras (PROTACs) target the Kirsten rat sarcoma virus-son of sevenless 1 (KRAS-SOS1) axis, offering potential for enhanced cancer treatment. These PROTACs degrade target proteins, showing promise beyond current KRAS G12C inhibitors.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- The KRAS-SOS1 axis is crucial for tumor growth in pancreatic, colon, and lung cancers.
- KRAS G12C inhibitors show limited efficacy and duration for treating KRAS-mutated tumors.
- Proteolysis-targeting chimeras (PROTACs) offer a novel approach to protein degradation for cancer therapy.
Purpose of the Study:
- To develop and evaluate PROTACs targeting the KRAS-SOS1 axis for improved cancer treatment.
- To assess the efficacy and potential limitations of KRAS- and SOS1-directed PROTACs.
Main Methods:
- Development of PROTACs by conjugating KRAS- or SOS1-directed inhibitors with VHL or CRBN ligands.
- In vitro and in vivo evaluation of PROTAC activity and efficacy.
- Investigation of resistance mechanisms to PROTACs, including E3 ligase inactivation.
Main Results:
- Several developed PROTACs demonstrated enhanced activity compared to their parent inhibitors in vitro and in vivo.
- Potential toxicity in normal tissues remains unclear for some PROTAC constructs.
- Resistance mechanisms involve downregulation or inactivation of CRBN or VHL E3 ligase components.
Conclusions:
- KRAS- and SOS1-directed PROTACs represent a promising strategy for enhancing antitumor activity against KRAS-driven cancers.
- Further research is needed to address PROTAC toxicity and overcome resistance mechanisms for clinical application.
- Clinical translation of these highly active PROTACs faces challenges that require further investigation.
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