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 IC 50 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.

Discovery of a Potent, Cooperative, and Selective SOS1 PROTAC ZZ151 with In Vivo Antitumor Efficacy in KRAS-Mutant Cancers

“…While we were preparing this manuscript, Bian et al. disclosed their inhibitor-based SOS1 PROTAC 6 by recruiting the E3 ligase CRBN …”

“…While we were preparing this manuscript, Bian et al disclosed their inhibitorbased SOS1 PROTAC 6 by recruiting the E3 ligase CRBN. 22 Herein, we report the design and characterization of our inhibitor-based SOS1 PROTACs which hijack the other most commonly recruited E3 ligase VHL. Systematic structural modification of the linker length and composition offers us a potent, fast, cooperative, and selective SOS1 degrader ZZ151 (8c).…”

Development of Son of Sevenless Homologue 1 (SOS1) Modulators To Treat Cancers by Regulating RAS Signaling

“…PPI docking analysis of BI-68BS -bound SOS1 and lenalidomide-bound cereblon. Adapted in part with permission from ref . Copyright 2022 American Chemical Society.…”

“…Among these, compound 49 with eight methylene units exhibited the most potent SOS1 17). 103 The search for the optimal length and conformation of linkers was rationally guided by the protein−protein docking of BI-68BS-bound SOS1 and lenalidomide-bound cereblon. This revealed that relatively short linkers were desirable, leading to the synthesis of 15 compounds.…”

PROTACs: A novel strategy for cancer drug discovery and development

“…[12][13][14][15][16][17][18] TPD has entered its third decade with both opportunities and challenges. [19][20][21][22][23][24][25][26][27][28] TPD techniques rely on the ubiquitin-proteasome system (UPS), which couples ubiquitylation, catalyzed by E1 activating enzyme, E2 conjugate enzyme and E3 ligase, and proteasome for degradation of target substrates. [29][30][31][32][33][34][35][36][37][38][39][40][41] The concept of PROTAC was first proposed in 2001, and the PROTAC technology has developed rapidly in the past 20 years.…”