New Potent Inhibitor of Transforming Growth Factor-Beta (TGFβ) Signaling that is Efficacious against Microsatellite Stable Colorectal Cancer Metastasis in Combination with Immune Checkpoint Therapy in Mice.

Blockade of the TGFβ signaling pathway has emerged from preclinical studies as a potential treatment to enhance the efficacy of immune checkpoint inhibition in advanced colorectal cancer (CRC) and several other types of cancer. However, clinical translation of first-generation inhibitors has shown little success. Here, we report the synthesis and characterization of HYL001, a potent inhibitor of TGFβ receptor 1 (ALK5), that is approximately 9 times more efficacious than the structurally related compound galunisertib, while maintaining a favorable safety profile.

Amino acids with fluorescent tetrazine ethers as bioorthogonal handles for peptide modification.

A set of 3-bromo-1,2,4,5-tetrazines with three distinct substitutions have been used as reagents for late-stage functionalization of small molecules through nucleophilic aromatic substitution. Spectroscopic studies of the products obtained proved that tetrazine ethers are intrinsically fluorescent. This fluorescence is lost upon inverse Electron-Demand Diels-Alder (iEDDA) cycloaddition with strained alkenes.

TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis.

Most patients with colorectal cancer die as a result of the disease spreading to other organs. However, no prevalent mutations have been associated with metastatic colorectal cancers. Instead, particular features of the tumour microenvironment, such as lack of T-cell infiltration, low type 1 T-helper cell (T1) activity and reduced immune cytotoxicity or increased TGFβ levels predict adverse outcomes in patients with colorectal cancer.