Related Experiment Video
Updated: Aug 19, 2025
Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies
Published on: September 30, 2016
Development of SOS1 Inhibitor-Based Degraders to Target KRAS-Mutant Colorectal Cancer
Yujia Bian1, Diego Alem2, Francisca Beato2
1Department of Chemistry, University of Central Florida, 4111 Libra Drive, Orlando, Florida 32816, United States.
Abstract:
Direct blockade of KRAS driver mutations in colorectal cancer (CRC) has been challenging. Targeting SOS1, a guanine nucleotide exchange factor, has arisen as an attractive approach for KRAS-mutant CRC. Here, we describe the development of novel SOS1 degraders and their activity in patient-derived CRC organoids (PDO). The design of these degraders as proteolysis-targeting chimera was based on the crystal structures of cereblon and SOS1. The synthesis used the 6- and 7-OH groups of a quinazoline core as anchor points to connect lenalidomide. Fifteen compounds were screened for SOS1 degradation. P7 was found to have up to 92% SOS1 degradation in both CRC cell lines and PDOs with excellent specificity. SOS1 degrader P7 demonstrated superior activity in inhibiting CRC PDO growth with an IC50 5 times lower than that of SOS1 inhibitor BI3406. In summary, we developed new SOS1 degraders and demonstrated SOS1 degradation as a feasible therapeutic strategy for KRAS-mutant CRC.
Insights
Researchers developed novel SOS1 degraders to target KRAS-mutant colorectal cancer (CRC). These compounds effectively degrade SOS1 in patient-derived organoids, showing promise as a new therapeutic strategy for CRC.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Directly targeting KRAS mutations in colorectal cancer (CRC) is difficult.
- SOS1, a guanine nucleotide exchange factor, is a potential therapeutic target for KRAS-mutant CRC.
Purpose of the Study:
- To develop novel SOS1 degraders.
- To evaluate the efficacy of these degraders in patient-derived CRC organoids (PDOs).
Main Methods:
- Designed proteolysis-targeting chimeras (PROTACs) based on crystal structures of cereblon and SOS1.
- Synthesized and screened fifteen SOS1 degrader compounds.
- Assessed SOS1 degradation and inhibition of CRC PDO growth.
Main Results:
- Compound P7 achieved up to 92% SOS1 degradation in CRC cell lines and PDOs with high specificity.
- SOS1 degrader P7 showed superior efficacy in inhibiting CRC PDO growth compared to SOS1 inhibitor BI3406.
- P7 exhibited a 5-fold lower IC50 value than BI3406.
Conclusions:
- Novel SOS1 degraders were successfully developed.
- SOS1 degradation is a viable therapeutic strategy for KRAS-mutant CRC.
- The developed degraders show significant potential for treating KRAS-mutant CRC.
More Related Videos
10:13A Multiplexed Luciferase-based Screening Platform for Interrogating Cancer-associated Signal Transduction in Cultured Cells
Published on: July 3, 2013
06:51Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer
Published on: July 21, 2018
