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Updated: Jun 27, 2025
Functionalized Spirocyclic Heterocycle Synthesis and Cytotoxicity Assay
Published on: February 9, 2021
Design, synthesis, and bioevaluation of SOS1 PROTACs derived from pyrido[2,3-d]pyrimidin-7-one-based SOS1 inhibitor
Kun Wang1, Zehui Zhou2, Xinyi Ma3
1School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China; Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
Abstract:
Oncogenic KRAS mutations drive an approximately 25 % of all human cancers. Son of Sevenless 1 (SOS1), a critical guanine nucleotide exchange factor, catalyzes the activation of KRAS. Targeting SOS1 degradation has engaged as a promising therapeutic strategy for KRAS-mutant cancers. Herein, we designed and synthesized a series of novel CRBN-recruiting SOS1 PROTACs using the pyrido[2,3-d]pyrimidin-7-one-based SOS1 inhibitor as the warhead. One representative compound 11o effectively induced the degradation of SOS1 in three different KRAS-mutant cancer cell lines with DC50 values ranging from 1.85 to 7.53 nM. Mechanism studies demonstrated that 11o-induced SOS1 degradation was dependent on CRBN and proteasome. Moreover, 11o inhibited the phosphorylation of ERK and displayed potent anti-proliferative activities against SW620, A549 and DLD-1 cells. Further optimization of 11o may provide us promising SOS1 degraders with favorable drug-like properties for developing new chemotherapies targeting KRAS-driven cancers.
Insights
Researchers developed novel PROTACs targeting SOS1 degradation for KRAS-mutant cancers. Compound 11o effectively degraded SOS1, inhibited ERK, and showed anti-proliferative effects, offering potential new cancer therapies.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- Oncogenic KRAS mutations are implicated in ~25% of human cancers.
- Son of Sevenless 1 (SOS1) is a guanine nucleotide exchange factor crucial for KRAS activation.
- Targeting SOS1 degradation presents a promising therapeutic strategy for KRAS-mutant cancers.
Purpose of the Study:
- To design and synthesize novel Proteolysis-Targeting Chimeras (PROTACs) that recruit CRBN to induce SOS1 degradation.
- To evaluate the efficacy of these novel SOS1 PROTACs in KRAS-mutant cancer cell lines.
Main Methods:
- Design and synthesis of novel pyrido[2,3-d]pyrimidin-7-one-based SOS1 inhibitors conjugated to a CRBN ligand.
- Assessment of SOS1 degradation using DC50 values in KRAS-mutant cancer cell lines.
- Mechanism studies involving CRBN and proteasome dependency.
- Evaluation of ERK phosphorylation inhibition and anti-proliferative activity.
Main Results:
- A series of novel CRBN-recruiting SOS1 PROTACs were synthesized.
- Compound 11o demonstrated potent SOS1 degradation in multiple KRAS-mutant cancer cell lines (DC50: 1.85–7.53 nM).
- 11o-induced SOS1 degradation was confirmed to be CRBN and proteasome-dependent.
- 11o inhibited ERK phosphorylation and exhibited significant anti-proliferative effects against SW620, A549, and DLD-1 cells.
Conclusions:
- Novel SOS1 PROTACs, exemplified by compound 11o, effectively induce SOS1 degradation.
- These findings support the development of SOS1 degraders as a potential therapeutic approach for KRAS-driven cancers.
- Further optimization of 11o could lead to drug candidates with favorable properties for new chemotherapies.
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