50851-02-0Relevant academic research and scientific papers
Fragment-Based Discovery of Irreversible Covalent Inhibitors of Cysteine Proteases Using Chlorofluoroacetamide Library
Miura, Chizuru,Shindo, Naoya,Okamoto, Kei,Kuwata, Keiko,Ojida, Akio
, p. 1074 - 1081 (2020/11/26)
Fragment-based approach combined with electrophilic reactive compounds is a powerful strategy to discover novel covalent ligands for protein target. However, the promiscuous reactivity often interferes with identification of the fragments possessing specific binding affinity to the targeted protein. In our study, we report the fragment-based covalent drug discovery using the chemically tuned weak reactivity of chlorofluoroacetamide (CFA). We constructed a small fragment library composed of 30 CFA-appended compounds and applied it to the covalent ligand screening for cysteine protease papain as a model protein target. Using the fluorescence enzymatic assay, we identified CFA-benzothiazole 30 as a papain inhibitor, which was found to irreversibly inactivate papain upon enzyme kinetic analysis. The formation of the covalent papain-30 adduct was confirmed using electrospray ionization mass spectrometry analysis. The activity-based protein profiling (ABPP) experiment using an alkynylated analog of 30 (i.e., 30-yne) revealed that 30-yne covalently labeled papain with high selectivity. These data demonstrate potential utility of the CFA-fragment library for de novo discovery of target selective covalent inhibitors.
Tumor-Activated Benzothiazole Inhibitors of Stearoyl-CoA Desaturase
Williams, Noelle S.,Gonzales, Stephen,Naidoo, Jacinth,Rivera-Cancel, Giomar,Voruganti, Sukesh,Mallipeddi, Prema,Theodoropoulos, Panayotis C.,Geboers, Sophie,Chen, Hong,Ortiz, Francisco,Posner, Bruce,Nijhawan, Deepak,Ready, Joseph M.
, p. 9773 - 9786 (2020/10/19)
A series of N-acyl benzothiazoles shows selective and potent cytotoxicity against cancer cell lines expressing cytochrome P450 4F11. A prodrug form is metabolized by cancer cells into an active inhibitor of stearoyl-CoA desaturase (SCD). Substantial variation on the acyl portion of the inhibitors allowed the identification of (R)-27, which balanced potency, solubility, and lipophilicity to allow proof-of-concept studies in mice. The prodrugs were activated inside the tumor, where they can arrest tumor growth. Together, these observations offer promise that a tumor-activated prodrug strategy might exploit the essentiality of SCD for tumor growth, while avoiding toxicity associated with systemic SCD inhibition.
