Friday, November 15, 2024

Scalable Thiol Reactivity Profiling Identifies Azetidinyl Oxadiazoles as Cysteine-Targeting Electrophiles

Fereshte Ghorbani, Shaochen You, Gennadii A. Grabovyi, Mannkyu Hong, Garrett Lindsey, Arnab K. Chatterjee, and Michael J. Bollong

Journal of the American Chemical Society 2024

DOI: 10.1021/jacs.4c05711

Cysteine reactive groups are a mainstay in the design of covalent drugs and probe molecules, yet only a handful of electrophiles are routinely used to target this amino acid. Here, we report the development of scalable thiol reactivity (STRP), a method which enables the facile interrogation of large chemical libraries for intrinsic reactivity with cysteine. High throughput screening using STRP identified the azetidinyl oxadiazole as a moiety that selectively reacts with cysteine through a ring opening-based mechanism, capable of covalently engaging cysteine residues broadly across the human proteome. We show the utility of this reactive group with the discovery of an azetidinyl oxadiazole containing a small molecule that augments the catalytic activity of the deubiquitinase UCHL1 in vitro and in cells by covalently modifying a cysteine distal to its enzymatic active site. This study adds a novel cysteine targeting group to the electrophilic lexicon and provides robust methodology to rapidly surveil libraries for reactivity with cysteine.

Covalent Plant Natural Product that Potentiates Antitumor Immunity

Misao Takemoto, Sara Delghandi, Masahiro Abo, Keiko Yurimoto, Minami Odagi, Vaibhav Pal Singh, Jun Wang, Reiko Nakagawa, Shin-ichi Sato, Yas...