Discovery of LHF418 as a new potent SOS1 PROTAC degrader.

Son of sevenless homolog 1 (SOS1) plays a pivotal role as a molecular switch in the conversion of GDP-bound inactive KRAS to its active GTP-bound form, making SOS1 a promising therapeutic target for KRAS-driven cancers. While the most advanced SOS1 inhibitor has processed to phase I clinical trial, the exploration of novel SOS1 targeting strategies with distinct modes of action remains required. By employing proteolysis targeting chimera (PROTAC) technology, we obtained a series of new SOS1 degraders. The representative compound LHF418 potently induced SOS1 degradation with a DC50 value of 209.4 nM and a Dmax value of over 80 %. Mechanistic studies have illuminated that compound LHF418 induced the formation of ternary complex involving SOS1-PROTAC-cereblon (CRBN) and triggered SOS1 protein degradation in a CRBN- and proteasome-dependent manner. In addition, compound LHF418 effectively inhibited KRAS-RAF-ERK signalling, leading to the suppression of colony formation in KRAS-driven cancer cells. Overall, compound LHF418 represents a new lead compound in the developing novel and potent therapy for the treatment of KRAS-driven cancers.

Stereoselective Construction of Unsymmetrically Linked Heterocycles via Palladium-Catalyzed Alkyne Insertion/Cycloimidoylation Cascade.

A novel strategy to access unsymmetrically linked heterocycles via palladium-catalyzed acylcycloimidoylation of alkyne-tethered carbamoyl chlorides with isocyanides has been developed. Functionalized isocyanides were successfully applied as imine-containing heterocycle precursors to capture the vinyl-PdII intermediate, which was generated from a syn-carbopalladation of alkyne, followed by subsequent intramolecular C-H bond activation/imidoylative Heck reactions. Methylene oxindoles within Z-tetrasubstituted olefins were obtained in high yields with excellent stereoselectivities. Broad functional groups were well tolerated under mild reaction conditions.

Discovery of LLC355 as an Autophagy-Tethering Compound for the Degradation of Discoidin Domain Receptor 1.

Discoidin domain receptor 1 (DDR1) is a potential target for cancer drug discovery. Although several DDR1 kinase inhibitors have been developed, recent studies have revealed the critical roles of the noncatalytic functions of DDR1 in tumor progression, metastasis, and immune exclusion. Degradation of DDR1 presents an opportunity to block its noncatalytic functions. Here, we report the discovery of the DDR1 degrader LLC355 by employing autophagosome-tethering compound technology. Compound LLC355 efficiently degraded DDR1 protein with a DC50 value of 150.8 nM in non-small cell lung cancer NCI-H23 cells. Mechanistic studies revealed compound LLC355 to induce DDR1 degradation via lysosome-mediated autophagy. Importantly, compound LLC355 potently suppressed cancer cell tumorigenicity, migration, and invasion and significantly outperformed the corresponding inhibitor 1. These results underline the therapeutic advantage of targeting the noncatalytic function of DDR1 over inhibition of its kinase activity.

Palladium-catalysed imidoylative spirocyclization of 3-(2-isocyanoethyl)indoles.

A palladium-catalysed construction of spiroindolines through dearomative spirocyclization of 3-(2-isocyanoethyl)indoles has been developed. 2'-Aryl-, vinyl-, and alkyl-substituted spiroindolines could be accessed under mild conditions with excellent functional group tolerance. C1-tethered oxindole- and indole-spiroindoline bisheterocycles were generated in high yields via alkene/allene insertion and an imidoylative spirocyclization cascade. Additionally, a tandem dearomatization of two different indoles was realized with N-(2-bromobenzoyl)indoles as the electrophilic coupling partner of 3-(2-isocyanoethyl)indoles, affording polyindoline - spiroindoline bisheterocyclic scaffolds conveniently. Under the catalysis of Pd(OAc)2 and a spinol-derived phosphoramidite ligand, chiral spiroindolines were successfully accessed with up to 95% yield and 85% ee.