We
report the discovery of N-substituted 4-(pyridin-2-yl)thiazole-2-amine
derivatives and their subsequent optimization, guided by structure-based
design, to give 8-(1H-pyrazol-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-ones, a series of potent
JmjC histone N-methyl lysine demethylase (KDM) inhibitors
which bind to Fe(II) in the active site. Substitution from C4 of the
pyrazole moiety allows access to the histone peptide substrate binding
site; incorporation of a conformationally constrained 4-phenylpiperidine
linker gives derivatives such as 54j and 54k which demonstrate equipotent activity versus the KDM4 (JMJD2) and
KDM5 (JARID1) subfamily demethylases, selectivity over representative
exemplars of the KDM2, KDM3, and KDM6 subfamilies, cellular permeability
in the Caco-2 assay, and, for 54k, inhibition of H3K9Me3 and H3K4Me3 demethylation in a cell-based assay.
The members of the NSD subfamily of lysine methyl transferases are compelling oncology targets due to the recent characterization of gain-of-function mutations and translocations in several hematological cancers. To date, these proteins have proven intractable to small molecule inhibition. Here, we present initial efforts to identify inhibitors of MMSET (aka NSD2 or WHSC1) using solution phase and crystal structural methods. On the basis of 2D NMR experiments comparing NSD1 and MMSET structural mobility, we designed an MMSET construct with five point mutations in the N-terminal helix of its SET domain for crystallization experiments and elucidated the structure of the mutant MMSET SET domain at 2.1 Å resolution. Both NSD1 and MMSET crystal systems proved resistant to soaking or cocrystallography with inhibitors. However, use of the close homologue SETD2 as a structural surrogate supported the design and characterization of N-alkyl sinefungin derivatives, which showed low micromolar inhibition against both SETD2 and MMSET.
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