Rational design and synthesis of a heterocycle scaffold for DNMT3A inhibition
Abstract
DNA methylation, a crucial epigenetic modification involved in human diseases, is catalyzed by DNA methyltransferases (DNMTs). This study presents a rational design strategy for developing DNMT3A-preferential inhibitors based on a cytosine-containing scaffold. Building on the most potent compound identified from enzymatic activity screening, MOE scaffold replacement was employed to generate a focused virtual library of 5287 analogs. Subsequent drug-likeness and synthetic accessibility filtering narrowed the set to 82 candidates. Among the synthesized derivatives, two lead compounds (6o and 6p) exhibited moderate preferential inhibition of DNMT3A over DNMT1 in enzymatic assays, showing IC50 values around 30 μM against DNMT3A, while only weak or no inhibition of DNMT1 was observed even at high concentrations (320 μM). Molecular dynamics simulations suggested stable binding of the compounds to DNMT3A. In addition, the two compounds demonstrated anti-proliferative effects in HCT116 colorectal cancer cells, with compound 6o showing greater potency. These findings highlight 6o and 6p as promising lead compounds for further development of DNMT3A selective inhibitors.
Related
- Enhancing the Activity of Ribokinase from Thermus sp. 2.9 Through Rational Design for the Cascade Synthesis of Modified Nucleotides and Nucleosides
- Total synthesis and structural characterization of a novel protein scaffold from the snail Biomphalaria glabrata
- Examining roles of varying synthesis and assembly conditions on the incorporation of complex multi-lipid extracts into membrane scaffold protein nanodiscs
- Rational design of L-Pantolactone dehydrogenase to enhance the activity of whole-cell biocatalyst
- Rational design of disordered proteins for sequence–function investigation
BibTeX
@article{chen2026rational,
title = {{Rational design and synthesis of a heterocycle scaffold for DNMT3A inhibition}},
author = {Ting Chen and Ahmad Elbahnsi and Elodie Olivier and Syrine Mahdadi and Corinne Jallet and Guilaine Nchugoua and Paola Arimondo and Maria Miteva and Stéphanie Desbène-Finck},
journal = {Bioorganic Chemistry},
year = {2026},
month = sep,
doi = {10.1016/j.bioorg.2026.110025},
url = {https://pasteur.hal.science/pasteur-05772388v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Rational design and synthesis of a heterocycle scaffold for DNMT3A inhibition
AU - Ting Chen
AU - Ahmad Elbahnsi
AU - Elodie Olivier
AU - Syrine Mahdadi
AU - Corinne Jallet
AU - Guilaine Nchugoua
AU - Paola Arimondo
AU - Maria Miteva
AU - Stéphanie Desbène-Finck
PY - 2026
DA - 2026/09/05
JO - Bioorganic Chemistry
DO - 10.1016/j.bioorg.2026.110025
UR - https://pasteur.hal.science/pasteur-05772388v1
AB - DNA methylation, a crucial epigenetic modification involved in human diseases, is catalyzed by DNA methyltransferases (DNMTs). This study presents a rational design strategy for developing DNMT3A-preferential inhibitors based on a cytosine-containing scaffold. Building on the most potent compound identified from enzymatic activity screening, MOE scaffold replacement was employed to generate a focused virtual library of 5287 analogs. Subsequent drug-likeness and synthetic accessibility filtering narrowed the set to 82 candidates. Among the synthesized derivatives, two lead compounds (6o and 6p) exhibited moderate preferential inhibition of DNMT3A over DNMT1 in enzymatic assays, showing IC50 values around 30 μM against DNMT3A, while only weak or no inhibition of DNMT1 was observed even at high concentrations (320 μM). Molecular dynamics simulations suggested stable binding of the compounds to DNMT3A. In addition, the two compounds demonstrated anti-proliferative effects in HCT116 colorectal cancer cells, with compound 6o showing greater potency. These findings highlight 6o and 6p as promising lead compounds for further development of DNMT3A selective inhibitors.
SN - 0045-2068
SN - 1090-2120
ER -