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. 2017 Jul 27;8(8):869-874.
doi: 10.1021/acsmedchemlett.7b00220. eCollection 2017 Aug 10.

Design of KDM4 Inhibitors with Antiproliferative Effects in Cancer Models

Young K Chen  1 , Tiziana Bonaldi  2 , Alessandro Cuomo  2 , Joselyn R Del Rosario  1 , David J Hosfield  3 , Toufike Kanouni  1 , Shih-Chu Kao  4 , Chon Lai  1 , Neethan A Lobo  4 , Jennifer Matuszkiewicz  1 , Andrew McGeehan  4 , Shawn M O'Connell  1 , Lihong Shi  1 , Jeffrey A Stafford  1 , Ryan K Stansfield  1 , James M Veal  1 , Michael S Weiss  4 , Natalie Y Yuen  4 , Michael B Wallace  1
Affiliations

Design of KDM4 Inhibitors with Antiproliferative Effects in Cancer Models

Young K Chen et al. ACS Med Chem Lett. .

Abstract

Histone lysine demethylases (KDMs) play a vital role in the regulation of chromatin-related processes. Herein, we describe our discovery of a series of potent KDM4 inhibitors that are both cell permeable and antiproliferative in cancer models. The modulation of histone H3K9me3 and H3K36me3 upon compound treatment was verified by homogeneous time-resolved fluorescence assay and by mass spectroscopy detection. Optimization of the series using structure-based drug design led to compound 6 (QC6352), a potent KDM4 family inhibitor that is efficacious in breast and colon cancer PDX models.

Keywords: Epigenetics; JMJD2; KDM4; cancer; histone demethylase; synthesis.

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Conflict of interest statement

The authors declare the following competing financial interest(s): Authors include employees of Celgene and/or stockholders of Celgene.

Figures

Chart 1
Chart 1. 2,4-Pyridine Carboxylic Acid, Compound 1, and GSK Inhibitor
Chart 2
Chart 2. Tetrahydronaphthalene Lead 2 and Enantiomers
Figure 1
Figure 1
Cocrystal structure of compound 3 in the KDM4A active site. PDB code 5VMP.
Figure 2
Figure 2
MS intensity-based quantitation of H3 modified peptides (9–17) and (27–40) from KYSE-150 cells treated with compound 3. Percent relative abundances (%RAs) were calculated for all differentially modified forms of peptides (9–17) and (27–40) (top and bottom, respectively). A significant increase (p < 0.01, two-sample t test) was detected for both K9me3 and K36me3 at 24 or 96 h of treatment, relative to the corresponding %RAs of untreated (NT) cells. Error bars represent the standard error of the mean from five technical replicates (Supplementary Table 2).
Scheme 1
Scheme 1. Synthesis of Compound 6
Reagents and conditions: (a) TMSCN, ZnI2, toluene, 60 °C; H2SO4, AcOH, H2O, 105 °C, 80%; (b) H2, Ru(OAc)2[S-binap], THF, MeOH, 77%, >96% ee; (c) BH3-THF, THF, 55 °C, 79%; (d) methyl 3-bromo-isonicotinate, Xantphos, Pd2(dba)3, Cs2CO3, toluene, 120 °C, 50%; (e) N-methyl-aniline, Xantphos, Pd2(dba)3, Cs2CO3, toluene, 128 °C, 79%; (f) 1 N NaOH, MeOH, 89%.
Figure 3
Figure 3
Cocrystal structure of compound 6 (QC6352) in the KDM4A active site. PDB code 5VGI.
Figure 4
Figure 4
(a) Mouse in vivo efficacy of compound 6 in BR0859f xenograft model, dosed BID on a 5-on/2-off schedule. The tumor volumes are reported as the mean of each eight-animal group ± SEM. (b) Compound 6 shows effects on TIC population in the BR0869f model. Each point represents the tumor volume of a mouse that was inoculated with dissociated cells (50, 500, or 1000 cells) from either the BRO869f xenograft study vehicle group or the 50 mg/kg BID group. The median value is depicted with a line.
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