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Probes and Prodrugs for Redox Biology

Cellular networks of redox reactions are crucial to driving and regulating cellular physiology, with key roles from metabolism to signaling, protein activity regulation, and gene transcription. These networks are also significantly deregulated in serious pathologies including cancer and inflammatory diseases. These redox networks tend to rely on a few key upstream players, from which reducing/oxidising equivalents are distributed to a much broader range of downstream substrates. Therefore, developing selective chemical tools to respond to the activity of these key redox players is of particular interest to understand their physiological dynamics, as well as to respond to their pathological deregulation. We mainly focus on the thioredoxin (Trx) network, with some work also towards other disulfide/dithiol-manifold systems such as the Grxs, GPxs, and PDIs. Developing small-molecule selective tools for these enzymes is a highly challenging prospect, because their chemistries are so similar, and because their activity and reactivity is strongly controlled by compartmentalisation and redox fluxes. Before our work, there were no validated chemical tools for these disulfide/dithiol-manifold species that are enzyme-selective in the cellular context. Our goal is to use modern chemical biology and rational mechanism-based design to tap the potential of redox-responsive small molecules, towards high-selectivity probes of redox physiology, and to image and treat redox-dysregulated diseases.

Our redox research is pioneering novel redox-responsive chemotypes that can be used in modular "trigger-cargo" constructs to activate imaging agents or drugs conditional on the activity of specific redox enzymes and proteins. In parallel, we are promoting systematic methods to assess redox selectivity in the cellular context, revealing the complexities that have blocked previous tool designs from achieving meaningful impacts in redox research. Our research programme includes novel chemotype development, their use for fluorogenic imaging probes, then their adaptation into toxogenic prodrugs for cellular testing, and lastly the adaptation of selected agents into in vivo anticancer prodrugs.

Oliver's 10 minute talk on redox probes at the ACS ChemBio 2021 seminar series is here (starts at 48 minutes).

In vivo anticancer efficacy of Trx-activated S6-type duocarmycin prodrugs, & in vitro benchmarking over 177 cell lines
(BioRxiv 2022)
The Best Duocarmycins: a structure/function-based analysis of this perfect cytotoxic prodrug cargo, plus A0 Poster overview
(JACS Au 2022; *Editors Choice)
Scalable regioselective syntheses of SeS6: multi-gram, minimal column, high-efficiency routes to supply high-throughput screens
(ChemRxiv 2022)

SeS6: The first Thioredoxin Reductase-selective probes, enabled by a regiospecific selenenylsulfide anchor
(Chem 2022)
S6x: The first Thioredoxin-selective probes, enabled by kinetic and thermodynamic tuning of 6-membered cyclic disulfides
(J Am Chem Soc 2021)
S50: Revealing and explaining the unselectivity of previous state-of-the-art 5-membered cyclic disulfide probes
(Nat Commun 2022)

Selective redox prodrugs patent 2
(WO 2022/214598 2021)
Selective redox prodrugs patent 1
(WO 2022/200347 2021)