@article{2ff4480a28a14f12b29eec63b0679842,
title = "Development of SOS1 Inhibitor-Based Degraders to Target KRAS-Mutant Colorectal Cancer",
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 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.",
author = "Yujia Bian and Diego Alem and Francisca Beato and Hogenson, {Tara L.} and Xinrui Yang and Kun Jiang and Jianfeng Cai and Ma, {Wen Wee} and Martin Fernandez-Zapico and Tan, {Aik Choon} and Lawrence, {Nicholas J.} and Fleming, {Jason B.} and Yu Yuan and Hao Xie",
note = "Funding Information: The prepared protein structures were used for protein–protein docking experiments in Rosetta 3.12. Protein–protein local docking protocol was applied to the structure coordinates in an input pdb file prepared for docking. The following scripts were used to generate 500 docking poses, from which the total score and interface score were retrieved from the output file. The distance between /A LBK 1103 O13 (BI68BS 6-methoxy group) and /C LVY 502 N17 (lenalidomide amino group) and the distance between /A LBK 1103 O14 (BI68BS 7-methoxy group) and /C LVY 502 N17 were measured. Molecular graphics and analyses performed with UCSF ChimeraX, developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco with support from National Institutes of Health R01-GM129325 and the Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases. Statistical analyses were performed using R packages and jamovi. Funding Information: This study was supported by the Moffitt Cancer Center Support Grant to H.X. and the Tissue Core, Proteomics and Metabolomics Core, and the Biostatistics and Bioinformatics Shared Resource at the H. Lee Moffitt Cancer Center & Research Institute, an NCI designated Comprehensive Cancer Center (P30-CA076292). This study was also supported in part by University of Central Florida to Y.Y. (CA265050) and Joan F. & Richard A. Abdoo Family Fund in Colorectal Cancer Research to M.F.-Z. The content is solely the responsibility of the authors and does not necessarily represent the official views of the sponsors or the H. Lee Moffitt Cancer Center & Research Institute or University of Central Florida, Mayo Clinic, and NCI. Publisher Copyright: {\textcopyright} 2022 American Chemical Society. All rights reserved.",
year = "2022",
month = dec,
day = "22",
doi = "10.1021/acs.jmedchem.2c01300",
language = "English (US)",
volume = "65",
pages = "16432--16450",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "24",
}