Discovery of Covalent Wild-Type Isocitrate Dehydrogenase 1 (IDH1) Inhibitors Targeting Cys269
- 1Imperial College London
Abstract
Isocitrate dehydrogenase 1 (IDH1) catalyses the interconversion of isocitrate and -ketoglutarate and is overexpressed in several cancers, supporting tumour survival and treatment resistance. Inhibitors targeting the oncogenic mutant forms of IDH1 also inhibit the wild-type (WT) protein, but lose substantial potency due to greater competition with native substrates (isocitrate and Mg2+). We hypothesised that a covalent inhibitor may be more effective at overcoming the higher substrate affinity of wild-type IDH1. Here, a covalent fragment-based approach was used to develop IDH1-C269 selective inhibitors which prevent the key regulatory segment from forming an -helix required for catalytic competency. Following the identification of C269-selective fragments, we used X-ray crystallography to characterise IDH1-fragment bound complexes and guide structure-based design efforts. Inspired by the unexpected detection of bound isocitrate molecule in an X-ray crystal structure, fragment expansion yielded a series of compounds exploiting both an adjacent site and a unique water-mediated hydrogen bonding network. This series achieved strong potency (reaching IC50 = 47.5 nM, a 155-fold improvement in potency relative to the original fragment), retained activity in the presence of competing Mg2+, showed selectivity against IDH2 and reduced NADPH concentrations in a relevant PDAC cell model. Together, these findings present a mechanistic rationale for the covalent targeting of wild-type IDH1 and provide structurally validated inhibitors for further development.
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BibTeX
@misc{brown2026discovery,
title = {{Discovery of Covalent Wild-Type Isocitrate Dehydrogenase 1 (IDH1) Inhibitors Targeting Cys269}},
author = {C. P. Brown and E. O. Harmer and A. Azam and C. Sharp and S. Horrell and J. A. Bull and A. Armstrong and D. Mann},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.24.753951},
url = {https://www.biorxiv.org/content/10.64898/2026.09.24.753951v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Discovery of Covalent Wild-Type Isocitrate Dehydrogenase 1 (IDH1) Inhibitors Targeting Cys269
AU - C. P. Brown
AU - E. O. Harmer
AU - A. Azam
AU - C. Sharp
AU - S. Horrell
AU - J. A. Bull
AU - A. Armstrong
AU - D. Mann
PY - 2026
DA - 2026/09/24
PB - bioRxiv
DO - 10.64898/2026.09.24.753951
UR - https://www.biorxiv.org/content/10.64898/2026.09.24.753951v1
AB - Isocitrate dehydrogenase 1 (IDH1) catalyses the interconversion of isocitrate and -ketoglutarate and is overexpressed in several cancers, supporting tumour survival and treatment resistance. Inhibitors targeting the oncogenic mutant forms of IDH1 also inhibit the wild-type (WT) protein, but lose substantial potency due to greater competition with native substrates (isocitrate and Mg2+). We hypothesised that a covalent inhibitor may be more effective at overcoming the higher substrate affinity of wild-type IDH1. Here, a covalent fragment-based approach was used to develop IDH1-C269 selective inhibitors which prevent the key regulatory segment from forming an -helix required for catalytic competency. Following the identification of C269-selective fragments, we used X-ray crystallography to characterise IDH1-fragment bound complexes and guide structure-based design efforts. Inspired by the unexpected detection of bound isocitrate molecule in an X-ray crystal structure, fragment expansion yielded a series of compounds exploiting both an adjacent site and a unique water-mediated hydrogen bonding network. This series achieved strong potency (reaching IC50 = 47.5 nM, a 155-fold improvement in potency relative to the original fragment), retained activity in the presence of competing Mg2+, showed selectivity against IDH2 and reduced NADPH concentrations in a relevant PDAC cell model. Together, these findings present a mechanistic rationale for the covalent targeting of wild-type IDH1 and provide structurally validated inhibitors for further development.
ER -