2. Academic Validation
  3. Development of SOS1 Inhibitor-Based Degraders to Target KRAS-Mutant Colorectal Cancer

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

  • J Med Chem. 2022 Dec 22;65(24):16432-16450. doi: 10.1021/acs.jmedchem.2c01300.
Yujia Bian 1,  Diego Alem 2,  Francisca Beato 2,  Tara L Hogenson 3,  Xinrui Yang 2,  Kun Jiang 4,  Jianfeng Cai 5,  Wen Wee Ma 6,  Martin Fernandez-Zapico 3,  Aik Choon Tan 7,  Nicholas J Lawrence 8,  Jason B Fleming 2,  Yu Yuan 1,  Hao Xie 2
Affiliations

Affiliations

  • 1 Department of Chemistry, University of Central Florida, 4111 Libra Drive, Orlando, Florida 32816, United States.
  • 2 Department of Gastrointestinal Oncology, H Lee Moffitt Cancer Center and Research Institute, 12902 USF Magnolia Drive, Tampa, Florida 33612, United States.
  • 3 Schulze Center for Novel Therapeutics, Department of Oncology, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, United States.
  • 4 Department of Pathology, H Lee Moffitt Cancer Center and Research Institute, 12902 USF Magnolia Drive, Tampa, Florida 33612, United States.
  • 5 Department of Chemistry, University of South Florida, 12111 USF Sweetgum Ln, Tampa, Florida 33620, United States.
  • 6 Division of Medical Oncology, Department of Oncology, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, United States.
  • 7 Department of Biostatistics and Bioinformatics, H Lee Moffitt Cancer Center and Research Institute, 12902 USF Magnolia Drive, Tampa, Florida 33612, United States.
  • 8 Department of Drug Discovery, H Lee Moffitt Cancer Center and Research Institute, 12902 USF Magnolia Drive, Tampa, Florida 33612, United States.
PMID: 36459180 DOI: 10.1021/acs.jmedchem.2c01300
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.

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