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Updated: May 7, 2026
Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs
Published on: May 15, 2019
Discovery of LHF418 as a new potent SOS1 PROTAC degrader
Huifan Li1, Minxue Chai2, Yihan Chen1
1State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China.
Abstract:
Son of sevenless homolog 1 (SOS1) plays a pivotal role as a molecular switch in the conversion of GDP-bound inactive KRAS to its active GTP-bound form, making SOS1 a promising therapeutic target for KRAS-driven cancers. While the most advanced SOS1 inhibitor has processed to phase I clinical trial, the exploration of novel SOS1 targeting strategies with distinct modes of action remains required. By employing proteolysis targeting chimera (PROTAC) technology, we obtained a series of new SOS1 degraders. The representative compound LHF418 potently induced SOS1 degradation with a DC50 value of 209.4 nM and a Dmax value of over 80 %. Mechanistic studies have illuminated that compound LHF418 induced the formation of ternary complex involving SOS1-PROTAC-cereblon (CRBN) and triggered SOS1 protein degradation in a CRBN- and proteasome-dependent manner. In addition, compound LHF418 effectively inhibited KRAS-RAF-ERK signalling, leading to the suppression of colony formation in KRAS-driven cancer cells. Overall, compound LHF418 represents a new lead compound in the developing novel and potent therapy for the treatment of KRAS-driven cancers.
Insights
New PROTAC degraders targeting Son of sevenless homolog 1 (SOS1) show promise for KRAS-driven cancers. The lead compound LHF418 effectively degrades SOS1 and inhibits cancer cell growth.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Son of sevenless homolog 1 (SOS1) is crucial for KRAS activation, making it a key target in KRAS-driven cancers.
- Existing SOS1 inhibitors are advancing, but novel strategies with different mechanisms are needed.
Purpose of the Study:
- To develop novel SOS1-targeting agents using proteolysis targeting chimera (PROTAC) technology.
- To evaluate the efficacy of new SOS1 degraders in preclinical cancer models.
Main Methods:
- Utilized PROTAC technology to design and synthesize novel SOS1 degraders.
- Characterized the lead compound LHF418 for its degradation potency (DC50, Dmax) and mechanism of action.
- Assessed the impact of LHF418 on KRAS-RAF-ERK signaling and cancer cell proliferation.
Main Results:
- Developed a series of SOS1 degraders, with LHF418 showing potent degradation (DC50 = 209.4 nM, Dmax > 80%).
- Confirmed LHF418 induces SOS1 degradation via a CRBN- and proteasome-dependent mechanism through ternary complex formation.
- LHF418 effectively inhibited KRAS-RAF-ERK signaling and suppressed colony formation in KRAS-driven cancer cells.
Conclusions:
- LHF418 is a potent SOS1 degrader with therapeutic potential for KRAS-driven cancers.
- PROTAC technology offers a promising approach for targeting SOS1 and developing novel cancer therapies.
