Development of SOS1 Inhibitor-Based Degraders to Target KRAS-Mutant Colorectal Cancer

Yujia Bian, Diego Alem, Francisca Beato, Tara L. Hogenson, Xinrui Yang, Kun Jiang, Jianfeng Cai, Wen Wee Ma, Martin Fernandez-Zapico, Aik Choon Tan, Nicholas J. Lawrence, Jason B. Fleming, Yu Yuan, Hao Xie

Research output: Contribution to journalArticlepeer-review


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 IC505 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.

Original languageEnglish (US)
Pages (from-to)16432-16450
Number of pages19
JournalJournal of Medicinal Chemistry
Issue number24
StatePublished - Dec 22 2022

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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