4‐Biphenylalanine‐ and 3‐Phenyltyrosine‐Derived Hydroxamic Acids as Inhibitors of the JumonjiC‐Domain‐Containing Histone Demethylase KDM4A

Abstract

Overexpression of the histone lysine demethylase KDM4A, which regulates H3K9 and H3K36 methylation states, has been related to the pathology of several human cancers. We found that a previously reported hydroxamate-based histone deacetylase (HDAC) inhibitor (SW55) was also able to weakly inhibit this demethylase with an IC50 value of 25.4 μm. Herein we report the synthesis and biochemical evaluations, with two orthogonal in vitro assays, of a series of derivatives of this lead structure. With extensive chemical modifications on the lead structure, also by exploiting the versatility of the radical arylation with aryldiazonium salts, we were able to increase the potency of the derivatives against KDM4A to the low-micromolar range and, more importantly, to obtain demethylase selectivity with respect to HDACs. Cell-permeable derivatives clearly showed a demethylase-inhibition-dependent antiproliferative effect against HL-60 human promyelocytic leukemia cells.

Tailored Mutants of Phenylalanine Ammonia‐Lyase from Petroselinum crispum for the Synthesis of Bulky l‐ and d‐Arylalanines

“…These compounds offer new possibilities to extend the chemical space available to biomedicine (peptides, proteins, peptidomimetics) and chiral small‐molecule drugs. The envisaged ([1,1′‐biphenyl]‐4‐yl)alanines are constituents of various bioactive peptides, such as peptidase, protease, and cancer‐related histone lysine demethylase KDM4A inhibitors. (Naphthalen‐2‐yl)alanine is used frequently as a phenylalanine analogue in the development of peptides, whereas (4‐methoxyphenyl)alanine is a chiral intermediate in the synthesis of the antihypertensive drug tamsulosin .…”

The Clinically Used Iron Chelator Deferasirox Is an Inhibitor of Epigenetic JumonjiC Domain-Containing Histone Demethylases

“…14 As JumonjiC KDMs use molecular oxygen as oxidizing agent for the demethylation reaction, a role in cellular oxygen sensing has also been discussed, e. g. for the subtype KDM6A. 15 JmjC histone demethylases have emerged as promising drug targets, 1,[16][17][18][19][20] with inhibitor discovery programs being reported by us [21][22][23][24][25][26][27] and others, [28][29][30][31][32][33][34][35] as recently reviewed. 17,19,[36][37][38][39][40] The majority of reported JmjC KDM inhibitors function by active site metal chelation and competitive displacement of the co-substrate 2OG.…”

“…None of the tested compounds were flagged as PAINS. Moreover, all compounds reported in this study were characterized in at least two in vitro assays with different readout techniques to provide orthogonal proof of their specific activities.Enzyme inhibition assays were performed as previously reported [21][22][23]. JMJD2A (KDM4A) FDH assay: The formaldehyde dehydrogenase (FDH) enzyme-coupled demethylase activity assay was performed in a total volume of 20 µL using white OptiPlate-384 microtiter plates (PerkinElmer) using a 50 mM HEPES buffer at pH = 7.50 containing 0.01%(v/v) Tween-20.…”

Small molecule KDM4s inhibitors as anti-cancer agents

“…Based on the scaffold of SW55, Jung et al. 85 synthesized a series of 4-biphenylaline and 3-phenyltyrosine derived hydroxamic acids as KDM4A inhibitors. The best compound 14 contained two hydroxamic acid moieties and exhibited potent inhibitory activity to KDM4A with IC 50 = 1.7 μM (LANCE assay).…”