Evidence / DNMT1

Mechanistic insight into new inhibitor chemistry.

Experimentally tested chemistry

Scientific case

DNMT1

Scientific question

How could mechanistic understanding guide differentiated, non-nucleoside inhibitor chemistry for a difficult enzyme target?

Kuano contribution

Transition-state characterisation informed the geometry, charge and interaction features used in a physics-based design model.

Design and evidence

The model guided exploration of new chemical matter. The programme produced differentiated inhibitor chemotypes with experimentally measured activity and differing selectivity profiles.

What the case establishes

A connection between mechanistic analysis, molecular design and experimental results. Potency and selectivity varied across chemotypes.

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All evidence

DNMT1 transition-state model showing methyl transfer from the cofactor to DNA — Transition-state model for DNMT1: methyl transfer from the cofactor to DNA, as labelled in the source figure. Kuano scientific case material. A computational model, not an experimental measurement.

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