20 August 2017

Fragments vs histone KDM4 lysine demethylases: Celgene’s story

Last year we highlighted a paper from academia in which modeling was used to discover potent inhibitors of the lysine demethylase KDM4C, a potential anti-cancer target. In a recent paper in ACS Med. Chem. Lett., Michael Wallace and collaborators at Celgene, the European Institute of Oncology, and the University of Chicago report a chemical probe for KDM4 family members.

The researchers started with a literature screen of fragments known to bind to KDM4, leading them to compound 1, which previous work had shown binds to the catalytic iron through the pyridine ring nitrogen. Researchers from GlaxoSmithKline had also reported that growing off compound 1 could lead to more potent compounds, a strategy that proved successful here in the case of chiral compound 2a, which improved affinity by more than two orders of magnitude. Interestingly, the enantiomer had dramatically lower activity.

Armed with this information but no crystal structure, modeling suggested that further growing off the tetrahydronaphthalene would be productive, which turned out to be the case for compound 3, with similar affinity but improved activity in an antiproliferative cell assay. Further experiments showed that the compound increased levels of trimethyl-lysine on lysines 9 and 36 of histone 3, known substrates of KDM4 family members.

A crystal structure of compound 3 bound to KDM4A, which is closely related to KDM4C, suggested further room to grow. Compound 3 contains a carboxylic acid and has a low cLogD, traits that tend to reduce cell permeability. The researchers thus focused on increasing the lipophilicity of the molecules, leading to QC6352. Despite the fact that this molecule is less potent in the enzymatic assay, it has significantly improved cellular potency. It also has reasonable pharmacokinetics and oral bioavailability, and showed activity in a mouse xenograft model. QC6352 hits KDM4A, 4B, 4C, and 4D, but is quite selective against most other KDMs.

This paper illustrates three important points. First, as discussed previously, you don’t need a novel fragment to get to novel leads – you just need creative scientists. Indeed, the increasing number of fragment hits reported for various targets provides a wealth of starting points even for organizations that don’t do in-house fragment screening. Second, you don’t necessarily need a crystal structure as long as you have good modelers. And finally, while excess lipophilicity is rightly avoided, it is important to remember that compounds can also be too polar. As Oscar Wilde noted, “everything in moderation, including moderation.”

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