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A Potent SOS1 PROTAC Degrader with Synergistic Efficacy in Combination with KRASG12C Inhibitor
Yan Lv1, Zixuan Yang1, Yiming Chen1
1Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, Shandong 266003, China.
Abstract:
AMG510, as the first approved inhibitor for KRASG12C mutation, has shown promising efficacy in nonsmall-cell lung cancer and colorectal cancer harboring KRASG12C mutation. However, the moderate response rate and the rapid emergence of acquired resistance limit the therapeutic potential of AMG510, highlighting the need for the development of combination strategies. Here, we observed the suppression of RAS-MAPK signaling induced by AMG510 was prolonged and enhanced by SOS1 knockdown. Thus, we design, synthesize, and characterize a potent and specific SOS1 degrader 23. Compound 23 showed efficient SOS1 degradation in KRAS-driven cancer cells and achieved significant antiproliferative potency. Importantly, the combination of 23 with AMG510 suppressed RAS signaling feedback activation, showing synergistic effects against KRASG12C mutant cells in vitro and in vivo. Our findings demonstrated that KRASG12C inhibition plus SOS1 degradation as a potential therapeutic strategy to improve antitumor response and overcome acquired resistance to KRASG12C inhibitor.
Insights
AMG510 is an effective KRASG12C inhibitor, but resistance limits its use. Combining AMG510 with a new SOS1 degrader (compound 23) enhances anti-cancer effects and overcomes resistance in KRASG12C-mutant cancers.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- AMG510 is the first approved inhibitor for KRASG12C mutations, showing efficacy in non-small cell lung and colorectal cancers.
- However, moderate response rates and acquired resistance limit AMG510's therapeutic potential, necessitating combination strategies.
Purpose of the Study:
- To investigate the potential of combining AMG510 with SOS1 inhibition to enhance anti-tumor activity.
- To design, synthesize, and characterize a novel SOS1 degrader (compound 23) for potential therapeutic use.
Main Methods:
- Investigated the effect of SOS1 knockdown on AMG510-induced RAS-MAPK signaling suppression.
- Designed, synthesized, and characterized compound 23, a specific SOS1 degrader.
- Evaluated the combination of compound 23 and AMG510 in KRASG12C-mutant cancer cells *in vitro* and *in vivo*.
Main Results:
- SOS1 knockdown prolonged and enhanced AMG510-induced RAS-MAPK signaling suppression.
- Compound 23 demonstrated efficient SOS1 degradation and significant antiproliferative activity in KRAS-driven cancer cells.
- The combination of compound 23 and AMG510 synergistically suppressed RAS signaling feedback activation and exhibited anti-tumor effects.
Conclusions:
- Combining KRASG12C inhibition with SOS1 degradation presents a promising therapeutic strategy.
- This combination approach may improve anti-tumor responses and overcome acquired resistance to KRASG12C inhibitors.
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