2. Academic Validation
  3. Discovery of LHF418 as a new potent SOS1 PROTAC degrader

Discovery of LHF418 as a new potent SOS1 PROTAC degrader

  • Bioorg Med Chem. 2024 Apr 1:103:117661. doi: 10.1016/j.bmc.2024.117661.
Huifan Li 1,  Minxue Chai 2,  Yihan Chen 1,  Fengtao Zhou 3,  Xiaomei Ren 1,  Jian Xu 4,  Jian Wang 5,  Zhen Wang 6,  Weixue Huang 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China.
  • 2 State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China; Key Laboratory of Functional Molecular Solids, Ministry of Education, Anhui Laboratory of Molecule-Based Materials, College of Chemistry and Materials Science, Anhui Normal University, Wuhu 241000, China.
  • 3 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, College of Pharmacy, Jinan University, Guangzhou 511400, China.
  • 4 Livzon Research Institute, Livzon Pharmaceutical Group Inc., Zhuhai 519000, China.
  • 5 Key Laboratory of Functional Molecular Solids, Ministry of Education, Anhui Laboratory of Molecule-Based Materials, College of Chemistry and Materials Science, Anhui Normal University, Wuhu 241000, China. Electronic address: [email protected].
  • 6 State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China; Ningbo Zhongke Creation Center of New Materials, Ningbo 315000, China. Electronic address: [email protected].
  • 7 State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China; Ningbo Zhongke Creation Center of New Materials, Ningbo 315000, China. Electronic address: [email protected].
PMID: 38489998 DOI: 10.1016/j.bmc.2024.117661
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.

Keywords

Antitumor; Degrader; KRAS; PROTAC; SOS1.

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