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.
An efficient and mild synthesis of a variety of 3-(2-oxopropyl)-isoindolinone derivatives via a BF·EtO catalyzed cascade reaction among 3-hydroxyisoindolin-1-one and phenylacetylene was achieved. Various isoindolinone derivatives were obtained in good to excellent yields. The process, which avoided several drawbacks such as the requirement of concentrated protic acids and metal catalysts, protecting group of nitrogen, high temperature, and multistep synthesis, includes C(sp)-OH cleavage, C-C coupling, and hydration of alkyne.
The diverse structures and profound biological activities of lignan natural products have enticed significant effort in the exploration of new methodologies for their total synthesis. We have prepared γ-butyrolactone oximes from readily available δ-nitro alcohols via Boc 2 O mediated cyclization. The mild conditions are compatible with a wide range of functional groups, and this methodology has been applied to the total synthesis of five lignan natural products.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.