# Structure-Guided Design of a KMT9 Inhibitor Prodrug with Cellular Activity

## TL;DR

Researchers designed a prodrug that effectively inhibits KMT9, a protein linked to cancer, showing promise for cancer therapy.

## Contribution

A prodrug was developed to overcome poor cellular activity of KMT9 inhibitors, demonstrating effective cancer cell inhibition.

## Key findings

- Branched cofactor analogues with methionine side chains are potent KMT9 inhibitors.
- Prodrug 8 shows cellular activity and blocks colon cancer cell proliferation.
- Structure-guided design improved potency and selectivity of KMT9 inhibitors.

## Abstract

Lysine methyltransferase 9 (KMT9), an obligate heterodimer
(KMT9α/KMT9β),
belongs to the few described Rossmann-fold histone lysine methyltransferases
and monomethylates histone H4 at lysine 12 (H4K12me1). KMT9 depletion
or inhibition impairs the proliferation of tumors, including prostate,
lung, colon, and bladder cancer cells, underscoring its therapeutic
potential. Here, we show the development of branched cofactor analogues
with a methionine side chain as highly potent KMT9 inhibitors. Through
structure-guided design, a basic nitrogen and 4-chlorophenoxy-2-fluorobenzene
in the substrate branch contribute most to the high potency and selectivity.
Due to the zwitterionic methionine side chain, the inhibitors did
not show cellular activity. Importantly, an ethyl ester prodrug 8 exhibits cellular target engagement and effectively blocks
the proliferation of colon cancer cell lines, further validating pharmacological
inhibition of KMT9 as a promising strategy for cancer therapy.