Publications by authors named "Jiangkun Yan"

5 Publications

  • Page 1 of 1

Design, synthesis, and biological evaluation of 5-aminotetrahydroquinoline-based LSD1 inhibitors acting on Asp375.

Arch Pharm (Weinheim) 2021 May 13:e2100102. Epub 2021 May 13.

Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China.

The abnormal expression of lysine-specific histone demethylase 1 (LSD1) is associated with different cancer types, and LSD1 inhibitory activity seems to have high therapeutic potential in cancer treatment. Here, we report the design, synthesis, and biochemical evaluation of novel 5-aminotetrahydroquinoline-based LSD1 inhibitors. Among them, compounds A6, A8, B1-B5, and C4 showed preferable inhibitory effects on LSD1, with IC  = 0.19-0.82 µM. Several potent compounds were selected to evaluate their antiproliferative activity on A549 cells and MCF-7 cells with a high expression of LSD1. The potential binding modes of the compounds were revealed through molecular docking to rationalize the potency of compounds toward LSD1. Our data recognized that the 5-aminotetrahydroquinoline scaffold may serve as a starting point for developing potent LSD1 inhibitors for cancer therapy.
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http://dx.doi.org/10.1002/ardp.202100102DOI Listing
May 2021

Design, synthesis and biological evaluation of novel benzofuran derivatives as potent LSD1 inhibitors.

Eur J Med Chem 2021 Aug 24;220:113501. Epub 2021 Apr 24.

Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning, China.

Lysine-specific demethylase 1 (LSD1) is a FAD-dependent enzyme, which has been proposed as a promising target for therapeutic cancer. Herein, a series of benzofuran derivatives were designed, synthesized and biochemical evaluated as novel LSD1 inhibitors based on scaffold hopping and conformational restriction strategy. Most of the compounds potently suppressed the enzymatic activities of LSD1 and potently inhibited tumor cells proliferation. In particular, the representative compound 17i exhibited excellent LSD1 inhibition at the molecular levels with IC = 0.065 μM, as well as anti-proliferation against MCF-7, MGC-803, H460, A549 and THP-1 tumor cells with IC values of 2.90 ± 0.32, 5.85 ± 0.35, 2.06 ± 0.27, 5.74 ± 1.03 and 6.15 ± 0.49 μM, respectively. The binding modes of these compounds were rationalized by molecular docking. Meanwhile, a preliminary druggability evaluation showed that compound 17i displayed favorable liver microsomal stability and weak inhibitory activity against CYPs at 10 μM. Remarkably, H460 xenograft tumors studies revealed that 17i demonstrated robust in vivo antitumor efficacy without significant side effects. All the results demonstrated that compound 17i could represent a promising lead for further development.
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http://dx.doi.org/10.1016/j.ejmech.2021.113501DOI Listing
August 2021

Design, synthesis and biological evaluation of tetrahydroquinoline-based reversible LSD1 inhibitors.

Eur J Med Chem 2020 May 21;194:112243. Epub 2020 Mar 21.

Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China.

The targeted regulation of LSD1, which is highly expressed in a variety of tumor cells, is a promising cancer therapy strategy. Several LSD1 inhibitors are currently under clinical evaluation, and most of these inhibitors are irreversible. Here, we report the design, synthesis and biochemical evaluation of novel tetrahydroquinoline-based reversible LSD1 inhibitors. Compounds 18s and 18x, which are selective to LSD1 over MAO-A/B, exhibit excellent LSD1 inhibition at the molecular levels with IC = 55 nM and 540 nM, respectively. The classic Lineweaver-Burk plots revealed that compound 18s could reversibly bind the LSD1 enzyme in a noncompetitive manner. Molecular docking was used to reveal the potential binding-mode of the compounds and interpret the structure-activity relationships. Furthermore, compounds 18s and 18x significantly inhibited proliferation (IC = 1.13 μM and 1.15 μM, respectively) and induced apoptosis in MGC-803 cells with high expression of LSD1. Compound 18x showed acceptable liver microsomal stability. Meanwhile, 18x did not appear to inhibit CYPs at 10 μM in vitro. Remarkably, the oral administration of compound 18x can inhibit the growth of MGC-803 xenograft tumors without significant side effects. Our findings suggest that tetrahydroquinoline-based LSD1 inhibitors deserve further investigation for the treatment of LSD1 overexpressing cancer.
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http://dx.doi.org/10.1016/j.ejmech.2020.112243DOI Listing
May 2020

Molecular docking, 3D-QSAR, and molecular dynamics simulations of thieno[3,2-b]pyrrole derivatives against anticancer targets of KDM1A/LSD1.

J Biomol Struct Dyn 2021 Mar 21;39(4):1189-1202. Epub 2020 Feb 21.

Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, P.R. China.

Lysine-specific demethylase 1 (LSD1) is a histone-modifying enzyme, which has been proposed as a promising target for anticancer drug development. Extensive research on LSD1 inhibitors has been performed since its discovery. In order to get more information for lead identification and optimization, we carried out a molecular modeling study on a set of 43 thieno[3,2-b]pyrrole competitive inhibitors of LSD1 using three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking and molecular dynamics (MD) simulations. Based on the co-crystallized conformer-based alignment (CCBA) method, 3D-QSAR model of thieno[3,2-b]pyrrole derivatives as LSD1 inhibitors was established. The significant statistics ( = 0.595, = 0.959, = 0.846) of the 3D-QSAR indicated the good predictive power and statistical reliability of this model. Based on the corresponding contour maps six LSD1 inhibitors were designed and their activities were predicted by 3D-QSAR model. Meanwhile, molecular docking was performed to simulate the probable binding modes between ligands and LSD1 protein. The molecular interactions mainly contributions to the binding affinity for LSD1 inhibitions were further supplemented by 100 ns MD simulations and binding free energy calculation.
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http://dx.doi.org/10.1080/07391102.2020.1726819DOI Listing
March 2021

Design, synthesis and biological evaluation of curcumin analogues as novel LSD1 inhibitors.

Bioorg Med Chem Lett 2019 12 13;29(23):126683. Epub 2019 Sep 13.

Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning, PR China.

Histone lysine-specific demethylase 1 (LSD1) was the first discovered histone demethylase. Inactivating LSD1 or downregulating its expression inhibits cancer-cell development, and thus, it is an attractive molecular target for the development of novel cancer therapeutics. In this study, we worked on the structural optimization of natural products and identified 30 novel LSD1 inhibitors. Utilizing a structure-based drug design strategy, we designed and synthesized a series of curcumin analogues that were shown to be potent LSD1 inhibitors in the enzyme assay. Compound WB07 displayed the most potent LSD1 inhibitory activity, with an IC value of 0.8 μM. Moreover, WA20 showed an anticlonogenic effect on A549 cells with an IC value of 4.4 μM. Molecular docking simulations were also carried out, and the results indicated that the inhibitors bound to the protein active site located around the key residues of Asp555 and Asp556. These findings suggested that compounds WA20 and WB07 are the first curcumin analogue-based LSD1 inhibitors with remarkable A549 suppressive activity, providing a novel scaffold for the development of LSD1 inhibitors.
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http://dx.doi.org/10.1016/j.bmcl.2019.126683DOI Listing
December 2019