# Electrochemical Nanoreactor Provides a Comprehensive View of Isocitrate Dehydrogenase Cancer‐drug Kinetics

## TL;DR

A new electrochemical method reveals detailed drug kinetics for a cancer-linked enzyme, providing insights into how inhibitors work.

## Contribution

The e-Leaf method enables detailed kinetic analysis of IDH1 R132H inhibition by anti-cancer drugs.

## Key findings

- Ivosidenib inhibits IDH1 R132H through a two-stage process involving rapid and slow binding steps.
- The e-Leaf method efficiently resolves inhibitor residence time and kinetic factors.
- The approach can be extended to study other enzyme systems with complex inhibition mechanisms.

## Abstract

The ability to control enzyme cascades entrapped in a nanoporous electrode material (the “Electrochemical Leaf”, e‐Leaf) has been exploited to gain detailed kinetic insight into the mechanism of an anti‐cancer drug. Ivosidenib, used to treat acute myeloid leukemia, acts on a common cancer‐linked variant of isocitrate dehydrogenase 1 (IDH1 R132H) inhibiting its “gain‐of‐function” activity—the undesired reduction of 2‐oxoglutarate (2OG) to the oncometabolite 2‐hydroxyglutarate (2HG). The e‐Leaf quantifies the kinetics of IDH1 R132H inhibition across a wide and continuous range of conditions, efficiently revealing factors underlying the inhibitor residence time. Selective inhibition of IDH1 R132H by Ivosidenib and another inhibitor, Novartis 224, is readily resolved as a two‐stage process whereby initial rapid non‐inhibitory binding is followed by a slower step to give the inhibitory complex. These kinetic features are likely present in other allosteric inhibitors of IDH1/2. Such details, essential for understanding inhibition mechanisms, are not readily resolved in conventional steady‐state kinetics or by techniques that rely only on measuring binding. Extending the new method and analytical framework presented here to other enzyme systems will be straightforward and should rapidly reveal insight that is difficult or often impossible to obtain using other methods.