Targeting Cysteine Located Outside the Active Site: An Effective Strategy for Covalent ALKi Design

Yan, Guohua; Zhong, Xinxin; Pu, Chun; Yang, Lin; Shan, Huifang; Lan, Suke; Hou, Xueyan; Yang, Jie; Li, Deyu; Fan, Shilong; Li, Rui

doi:10.1021/acs.jmedchem.0c01707

Cited by 7 publications

(7 citation statements)

References 29 publications

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“…17) Among the four compounds with strong activities, 1 had the largest number of functional groups, including four exo-olefins and two hydroxy groups. To gain further insight into the important structural features in 1; we synthesized six derivatives (22)(23)(24)(25)(26)(27) and evaluated their antiproliferative activities against U-251 MG CSCs and U-251 MG non-CSCs (Fig. 2).…”

Section: Synthesis Of Cynaropicrin Derivatives and Evaluation Of Sesq...mentioning

confidence: 99%

“…[11][12][13][14][15][16] A recent study has shown that 1 is strongly cytotoxic against human continuous glioblastoma U-87 MG cells. 17) Therefore, we synthesized six derivatives (22)(23)(24)(25)(26)(27), evaluated their antiproliferative activities against U-251 MG CSCs and U-251 MG non-CSCs, and determined the structural features that are important for such activities. We discussed the structure-activity relationships (SARs) and the antiproliferative activities of a total of 27 sesquiterpenoids, including six derivatives of 1, against U-251 MG CSCs and U-251 MG non-CSCs.…”

Section: Introductionmentioning

confidence: 99%

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Antiproliferative Activities of Cynaropicrin and Related Compounds against Cancer Stem Cells

Araki,

Hara,

Hamada

et al. 2024

Chem. Pharm. Bull.

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Glioblastoma (GBM) has a high mortality rate despite the availability of various cancer treatment options. Although cancer stem cells (CSCs) have been associated with poor prognosis and metastasis, and play an important role in the resistance to existing anticancer drugs and radiation; no CSC-targeting drugs are currently approved in clinical practice. Therefore, the development of antiproliferative agents against CSCs is urgently required. In this study, we evaluated the antiproliferative activities of 21 sesquiterpenoids against human GBM U-251 MG CSCs and U-251 MG non-CSCs. Particularly, the guaianolide sesquiterpene lactone cynaropicrin (1) showed strong antiproliferative activity against U-251 MG CSCs (IC 50 20.4 µM)and U-251 MG non-CSCs (IC 50 10.9 µM). Accordingly, we synthesized six derivatives of 1 and investigated their structure-activity relationships. Most of the guaianolide sesquiterpene lactones with the α-methylene-γbutyrolactone moiety showed antiproliferative activities against U-251 MG cells. We conclude that the 5,7,5-ring and the α-methylene-γ-butyrolactone moiety are both important for antiproliferative activities against U-251 MG cells. The results of this study suggest that the α,β-unsaturated carbonyl moiety, which has recently become a research hotspot in drug discovery, is the active center of 1. Therefore, we consider 1 as a potential lead for developing novel drugs targeting CSCs.

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Section: Synthesis Of Cynaropicrin Derivatives and Evaluation Of Sesq...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Antiproliferative Activities of Cynaropicrin and Related Compounds against Cancer Stem Cells

Araki,

Hara,

Hamada

et al. 2024

Chem. Pharm. Bull.

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“…Michael reaction acceptors (MRAs) have recently become importan chemical biological tools and are much of value in specific drug discovery programs. [1][2][3][4][5] Typically, MRAs contain an electrophilic group (such as, α ,β -unsaturated ketone moiety) suitably positioned to react with nucleophilic amino acids, generally a cysteine or lysine in the target protein and form a covalent bond. In the past decade, encouraged by the development of diverse electrophilic functional groups for MRA design and knowledge on the abundant accessible cysteine residues, seven MRAs have been approved by the FDA, such as afatinib and ibrutinib.…”

Section: Background and Originality Contentmentioning

confidence: 99%

Discovery of Michael reaction acceptors from the leaves of Ai-lanthus altissima by a modified tactic

Duan

Guo

et al. 2023

Preprint

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Structural characteristics-guided investigation of Ailanthus altissima (Mill.) Swingle resulted in the isolation and identification of seven undescribed potential Michael reaction acceptors (1–7). Ailanlactone A (1) possesses an unusual 1,7-epoxy-11,12-seco quassinoid core. Ailanterpene B (6) was a rare guaianolide-type sesquiterpene with a 5/6/6/6-fused skeleton. Their structures were determined through extensive analysis of physiochemical and spectroscopic data, quantum chemical calculations, and single crystal X-ray crystallo-graphic technology using Cu Kα radiation. The cytotoxic activities against HepG2 and Hep3B cells of isolates were determined. En-couragingly, ailanaltiolide K (4) showed significant cytotoxicity against Hep3B cells with IC50 values of 1.41 ± 0.21 μM, whose covalent binding mode was uncovered in silico.

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“…Yan et al. reported the development of Con B‐1 ( 40 ) which can covalently bind to Cys1259, a cysteine located outside the ALK active site [129] . The compounds was designed by linking a warhead with Ceritinib through a 2,2′‐Oxybis(ethylamine) linker.…”

Section: Kinase Inhibitors For Tackling Nsclcmentioning

confidence: 99%

Next‐Generation Kinase Inhibitors Targeting Specific Biomarkers in Non‐Small Cell Lung Cancer (NSCLC): A Recent Overview

2021

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Lung cancer causes many deaths globally. Mutations in regulatory genes, irregularities in specific signal transduction events, or alterations of signalling pathways are observed in cases of non‐small cell lung cancer (NSCLC). Over the past two decades, a few kinases have been identified, validated, and studied as biomarkers for NSCLC. Among them, EGFR, ALK, ROS1, MET, RET, NTRK, and BRAF are regarded as targetable biomarkers to cure and/or control the disease. In recent years, the US Food and Drug Administration (FDA) approved more than 15 kinase inhibitors targeting these NSCLC biomarkers. The kinase inhibitors significantly improved the progression‐free survival (PFS) of NSCLC patients. Challenges still remain for metastatic diseases and advanced NSCLC cases. New discoveries of potent kinase inhibitors and rapid development of modern medical technologies will help to control NSCLC cases. This article provides an overview of the discoveries of various types of kinase inhibitors against NSCLC, along with medicinal chemistry aspects and related developments in next‐generation kinase inhibitors that have been reported in recent years.

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Targeting Cysteine Located Outside the Active Site: An Effective Strategy for Covalent ALKi Design

Cited by 7 publications

References 29 publications

Antiproliferative Activities of Cynaropicrin and Related Compounds against Cancer Stem Cells

Antiproliferative Activities of Cynaropicrin and Related Compounds against Cancer Stem Cells

Discovery of Michael reaction acceptors from the leaves of Ai-lanthus altissima by a modified tactic

Next‐Generation Kinase Inhibitors Targeting Specific Biomarkers in Non‐Small Cell Lung Cancer (NSCLC): A Recent Overview

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