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. 2019 Feb 8;10(5):778-790.
doi: 10.1039/c8md00610e. eCollection 2019 May 1.

Dual inhibitors of LSD1 and spermine oxidase

Affiliations

Dual inhibitors of LSD1 and spermine oxidase

Steven Holshouser et al. Medchemcomm. .

Abstract

We have previously described the synthesis and evaluation of 3,5-diamino-1,2,4-triazole analogues as inhibitors of the flavin-dependent histone demethylase LSD1. These compounds are potent inhibitors of LSD1 without activity against monoamine oxidases A and B, and promote the elevation of H3K4me2 levels in tumor cells in vitro. We now report that the cytotoxicity of these analogues in pancreatic tumor cells correlates with the overexpression of LSD1 in each tumor type. In addition, we show that a subset of these 3,5-diamino-1,2,4-triazole analogues inhibit a related flavin-dependent oxidase, the polyamine catabolic enzyme spermine oxidase (SMOX) in vitro.

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Figures

Fig. 1
Fig. 1. Structures of known LSD1 inhibitors 1–7.
Scheme 1
Scheme 1
Scheme 2
Scheme 2
Fig. 2
Fig. 2. Determination of the IC50 values for inhibition of LSD1/CoREST by compounds 30 and 31. Each data point is the average of three determinations ± SEM.
Fig. 3
Fig. 3. Predictive QSAR model for LSD1 inhibitor library. New and previously reported small molecule competitive inhibitor IC50 values were entered into MOE to develop a predictive QSAR model. The model used various chemical descriptors vs. IC50 values to allow the prediction of future inhibitors.
Fig. 4
Fig. 4. Growth inhibition by SMOX in the Miapaca2 and BxPC-3 pancreatic tumor cell lines is related to the degree of overexpression of SMOX. Panel A: expression of SMOX in 3 pancreatic tumor cell lines and in CRL7869 intestinal epithelial cells as determined by western blot. Each data point is the average of 3 determinations ± SEM; panel B: immunohistochemical staining of human pancreatic tissue slices from cancerous (left) and non-cancerous patients; panel C: response of Miapaca2 pancreatic tumor cells to 5, gemcitabine, 30, 55 and 61; panel C: response of BxPC-3 pancreatic tumor cells to 5, gemcitabine, 30, 55 and 61. For panels C and D, each data point is the average of three determinations ± SEM.

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