Design, synthesis and biological evaluation of [1,2,4]triazolo[1,5-a]pyrimidines as potent lysine specific demethylase 1 (LSD1/KDM1A) inhibitors

Wang, Shuai; Zhao, Lijie; Zheng, Yi-Chao; Shen, Dan‐Dan; Miao, Er-Fei; Qiao, Xue-Peng; Zhao, Lijuan; Liu, Ying; Huang, Ruilei; Yu, Bin; Liu, Hong-Min

doi:10.1016/j.ejmech.2016.10.021

Cited by 65 publications

(22 citation statements)

References 35 publications

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“…Further mechanistic studies showed compound 7 inhibited cell migration and evasion, induced apoptosis and robustly suppressed growth of MGC-803 cells overexpressing LSD1 in vivo without significant toxicity. Following this work, our group recently performed extensive SARs studies using the scaffold hopping and bioisosteric replacement strategies, leading to the discovery of new LSD1 inhibitors 8 and 9, which reversibly inhibited LSD1 with the IC 50 values of 154 and 564 nM [57,58]. Compound 8 concentrationdependently inhibited migration of A549 and PC-9 future science group Advances toward LSD1 inhibitors for cancer therapy Review cells, but exerted different effects on the expression levels of E-cadherin and N-cadherin.…”

Section: Glu 379mentioning

confidence: 99%

Advances Toward Lsd1 Inhibitors for Cancer Therapy

Zhang

2017

Future Med. Chem.

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112

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LSD1 has become an important biologically validated epigenetic target for cancer therapy since its identification in 2004. LSD1 mediates many cellular signaling pathways and is involved in the initiation and development of cancers. Aberrant overexpression of LSD1 has been observed in different types of cancers, and inactivation by small molecules suppresses cancer cell differentiation, proliferation, invasion and migration. To date, a large number of LSD1 inhibitors have been reported, RG6016, GSK-2879552, INCB059872, IMG-7289 and CC-90011 are currently undergoing clinical assessment for the treatment of acute myeloid leukemia, small-cell lung cancer, etc. In this review, we briefly highlight recent advances of LSD1 inhibitors mainly covering the literatures from 2015 to 2017 and tentatively propose our perspectives on the design of new LSD1 inhibitors for cancer therapy.

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Section: Glu 379mentioning

confidence: 99%

Advances Toward Lsd1 Inhibitors for Cancer Therapy

Zhang

2017

Future Med. Chem.

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112

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“…All the compounds synthesized in this study were examined for their in vitro inhibitory effect toward LSD1, and GSK2879552 was chosen as a positive control46., 47.. The results were summarized in Table 1, Table 2, Table 3, Table 4.…”

Section: Resultsmentioning

confidence: 99%

“…Following our previous work on the identification of reversible LSD1 inhibitors43., 44., 45., 46., 47., here we describe the identification of triazole-fused pyrimidine-based reversible LSD1 inhibitors through the biochemical screening of our in-house structurally diverse molecular library ( ca. 500 compounds) and subsequent extensive medicinal chemistry efforts, leading to the identification of highly potent and selective LSD1 inhibitors (Fig.…”

Section: Introductionmentioning

confidence: 99%

Development of the triazole-fused pyrimidine derivatives as highly potent and reversible inhibitors of histone lysine specific demethylase 1 (LSD1/KDM1A)

Ding

et al. 2019

Acta Pharmaceutica Sinica B

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Histone lysine specific demethylase 1 (LSD1) has been recognized as an important modulator in post-translational process in epigenetics. Dysregulation of LSD1 has been implicated in the development of various cancers. Herein, we report the discovery of the hit compound 8a (IC 50 = 3.93 μmol/L) and further medicinal chemistry efforts, leading to the generation of compound 15u (IC 50 = 49 nmol/L, and K i = 16 nmol/L), which inhibited LSD1 reversibly and competitively with H3K4me2, and was selective to LSD1 over MAO-A/B. Docking studies were performed to rationalize the potency of compound 15u . Compound 15u also showed strong antiproliferative activity against four leukemia cell lines (OCL-AML3, K562, THP-1 and U937) as well as the lymphoma cell line Raji with the IC 50 values of 1.79, 1.30, 0.45, 1.22 and 1.40 μmol/L, respectively. In THP-1 cell line, 15u significantly inhibited colony formation and caused remarkable morphological changes. Compound 15u induced expression of CD86 and CD11b in THP-1 cells, confirming its cellular activity and ability of inducing differentiation. The findings further indicate that targeting LSD1 is a promising strategy for AML treatment, the triazole-fused pyrimidine derivatives are new scaffolds for the development of LSD1/KDM1A inhibitors.

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“…Wang et al. designed and synthesized pyrazolo[1,5- a ]pyrimidine derivatives as potent LSD1/KDM1A inhibitors [ 96 ]. Compounds 87a-c and 88a-b ( Fig.…”

Section: Biological Activities Of 124-triazole Derivativesmentioning

confidence: 99%

An insight on medicinal attributes of 1,2,4-triazoles

Aggarwal

Sumran²

2020

European Journal of Medicinal Chemistry

197

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The present review aims to summarize the pharmacological profile of 1,2,4-triazole, one of the emerging privileged scaffold, as antifungal, antibacterial, anticancer, anticonvulsant, antituberculosis, antiviral, antiparasitic, analgesic and anti-inflammatory agents, etc. along with structure-activity relationship. The comprehensive compilation of work carried out in the last decade on 1,2,4-triazole nucleus will provide inevitable scope for researchers for the advancement of novel potential drug candidates having better efficacy and selectivity.

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Design, synthesis and biological evaluation of [1,2,4]triazolo[1,5-a]pyrimidines as potent lysine specific demethylase 1 (LSD1/KDM1A) inhibitors

Cited by 65 publications

References 35 publications

Advances Toward Lsd1 Inhibitors for Cancer Therapy

Advances Toward Lsd1 Inhibitors for Cancer Therapy

Development of the triazole-fused pyrimidine derivatives as highly potent and reversible inhibitors of histone lysine specific demethylase 1 (LSD1/KDM1A)

An insight on medicinal attributes of 1,2,4-triazoles

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