Optimisation of a triazolopyridine based histone demethylase inhibitor yields a potent and selective KDM2A (FBXL11) inhibitor

Abstract

A potent inhibitor of the JmjC histone lysine demethylase KDM2A (compound 35, pIC50 7.2) with excellent selectivity over representatives from other KDM subfamilies has been developed; the discovery that a triazolopyridine compound binds to the active site of JmjC KDMs was followed by optimisation of the triazole substituent for KDM2A inhibition and selectivity.

Structure‐Based Screening of Tetrazolylhydrazide Inhibitors versus KDM4 Histone Demethylases

“…Among other reported KDM4 inhibitors, the most similar moiety to tetrazole is a triazole, which has been incorporated into a pyridine carboxylate scaffold. Many such derivatives have been synthesized and tested . However, their spatial position and orientation in the active site of the KDM4 enzymes is very different from that observed in the ligands reported herein.…”

Design and Synthesis of Quenched Activity‐based Probes for Diacylglycerol Lipase and α,β‐Hydrolase Domain Containing Protein 6

“…Pivaloyloxymethyl‐azide (POM‐N 3, Scheme ) . This procedure was adapted from literature . To a solution of NaN 3 (0.44 g, 6.6 mmol) in H 2 O (3.5 mL) was added POM‐Cl (0.85 mL, 6 mmol).…”

“…[40] 1 Ha nd 13 CNMR spectra were recorded on aB ruker AV-400 MHz spectrometer at 400 ( 1 H) and 100 ( Pivaloyloxymethyl-azide (POM-N 3, Scheme 1).T his procedure was adapted from literature. [41] To as olution of NaN 3 (0.44 g, 6.6 mmol) in H 2 O( 3.5 mL) was added POM-Cl (0.85 mL, 6mmol). The resulting mixture was stirred vigorously at 90 8Cf or 18 h. The reaction mixture was diluted with water and extracted with DCM (3x).…”

Advances in the development of histone lysine demethylase inhibitors

“…KDM6B is involved in macrophage differentiation in inflammatory response, brainstem glioma, and T-ALL [40 ,41 ,42]. Mutations in KDM6A have been associated with Kabuki syndrome but the gene is also frequently mutated in cancer and appears to act as a tumor suppressor in T-ALL [43] and myeloid malignancies, [54], SD70 [34 ], ML324 [33]; the pyridine derivatives Compound 35 [21], JIB-04 [55 ], GSK-J1/4 [40 ]) and C-70 [WO 2014053491]); and the hydroxamic acid derivative Compound 9 [46]. The main targets for each compound are reflected, but currently only the selective KDM1A inhibitors meet the criteria for bona fide chemical probes.…”

“…Treatment with 2 mM daminozide incremented H3K9 methylation in melanoma cells to similar levels as siRNA mediated KDM7 knockdown[20], reflecting good cell penetration. The substituted triazolopyridine, Compound 35, was identified as a KDM2A and likely KDM7 inhibitor with a much superior biochemical potency IC50 of 63 nM, 30Â selectivity over KDM5C and excellent selectivity over members of the KDM3, 4 and 6 subfamily[21], however cell potency was not reported.…”