Discovery and Synthesis of a Pyrimidine-Based Aurora Kinase Inhibitor to Reduce Levels of MYC Oncoproteins

Chi, Ya‐Hui; Yeh, Teng‐Kuang; Ke, Yi‐Yu; Lin, Wenye; Tsai, Chuen Jinn; Wang, Wan-Ping; Chen, Yen‐Ting; Su, Yu‐Chieh; Wang, Pei-Chen; Chen, Yan-Fu; Wu, Zhongwei; Yeh, Jen-Yu; Hung, Ming-Chun; Wu, Mine-Hsine; Wang, Jingya; Chen, Ching-Ping; Song, Jen‐Shin; Shih, Chuan; Chen, Chiung‐Tong; Chang, C. P.

doi:10.1021/acs.jmedchem.0c01806

Cited by 10 publications

(3 citation statements)

References 44 publications

(90 reference statements)

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“…[48,86,87] SCLC-N SCLC-N is an NE MYC high tumor with susceptibility to AURK inhibitors (AURKi). [73,88] The A-type AURK stabilizes the MYC family of oncoproteins, which have long been considered an undruggable target. It has been confirmed that AURKi can potently inhibit the proliferation of high-MYC-expressing SCLC cell lines.…”

Section: Sclc-amentioning

confidence: 99%

“…It has been confirmed that AURKi can potently inhibit the proliferation of high-MYC-expressing SCLC cell lines. [88] In a phase I/II study, single-agent treatment with alisertib, an investigational AURKi, showed an objective response rate of 21% (10/48) in patients with SCLC. [89] In another phase I study, the combination of alisertib with nab-paclitaxel proved to be synergistically active against rapidly proliferative high-grade NE tumors, especially SCLC, and displayed a manageable side-effect profile.…”

Section: Sclc-amentioning

confidence: 99%

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Molecular classification of small cell lung cancer subtypes: Characteristics, prognostic factors, and clinical translation

Guo,

Li,

Guo

et al. 2023

Chinese Medical Journal

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Small cell lung cancer (SCLC) is a highly malignant tumor with a very poor prognosis; therefore, more effective treatments are urgently needed for patients afflicted with the disease. In recent years, emerging molecular classifications based on key transcription factors of SCLC have provided more information on the tumor pathophysiology, metastasis, immune microenvironment, and acquired therapeutic resistance and reflected the intertumoral heterogeneity of the various SCLC phenotypes. Additionally, advances in genomics and single-cell sequencing analysis have further revealed the high intratumoral heterogeneity and plasticity of the disease. Herein, we review and summarize these recent lines of evidence and discuss the possible pathogenesis of SCLC.

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Section: Sclc-amentioning

confidence: 99%

Section: Sclc-amentioning

confidence: 99%

Molecular classification of small cell lung cancer subtypes: Characteristics, prognostic factors, and clinical translation

Guo,

Li,

Guo

et al. 2023

Chinese Medical Journal

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“…One of the compounds in this series reduced cMYC and MYCN levels by >50% at 1.0 μM. [ 58 ] These scaffolds thus exhibited sufficient evidence making them attractive molecules for further cancer drug development research. Investigators have published numerous synthetic strategies for synthesizing pyrimidine derivatives.…”

Section: Conclusion and Future Prospectsmentioning

confidence: 99%

Synthetic Strategies of Pyrimidine-Based Scaffolds as Aurora Kinase and Polo-like Kinase Inhibitors

et al. 2021

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The past few decades have witnessed significant progress in anticancer drug discovery. Small molecules containing heterocyclic moieties have attracted considerable interest for designing new antitumor agents. Of these, the pyrimidine ring system is found in multitude of drug structures, and being the building unit of DNA and RNA makes it an attractive scaffold for the design and development of anticancer drugs. Currently, 22 pyrimidine-containing entities are approved for clinical use as anticancer drugs by the FDA. An exhaustive literature search indicates several publications and more than 59 patents from the year 2009 onwards on pyrimidine derivatives exhibiting potent antiproliferative activity. These pyrimidine derivatives exert their activity via diverse mechanisms, one of them being inhibition of protein kinases. Aurora kinase (AURK) and polo-like kinase (PLK) are protein kinases involved in the regulation of the cell cycle. Within the numerous pyrimidine-based small molecules developed as anticancer agents, this review focuses on the pyrimidine fused heterocyclic compounds modulating the AURK and PLK proteins in different phases of clinical trials as anticancer agents. This article aims to provide a comprehensive overview of synthetic strategies for the preparation of pyrimidine derivatives and their associated biological activity on AURK/PLK. It will also present an overview of the synthesis of the heterocyclic-2-aminopyrimidine, 4-aminopyrimidine and 2,4-diaminopyrimidine scaffolds, and one of the pharmacophores in AURK/PLK inhibitors is described systematically.

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Synthesis, anticancer evaluation and docking studies of novel adamantanyl-1,3,4-oxadiazol hybrid compounds as Aurora-A kinase inhibitors

Jaber,

Al-Mahadeen,

Al-Qawasmeh

et al. 2023

Med Chem Res

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Cancer is a devastating disease, but advancements in cancer treatment offer hope for the future. Aurora Kinases are a family of serine/threonine kinases that play critical roles in cell cycle control and mitosis. There are three members of the Aurora kinase family in humans: Aurora-A kinase, Aurora-B kinase, and Aurora-C kinase. This study focuses on the synthesis of hybrid compounds combining adamantane and 1,3,4-oxadiazole as potential inhibitors of Aurora-A kinase. A series of novel 4- ((5-((3r,5r,7r)-adamantan-1yl)-1,3,4-oxadiazol-2-yl)thio)-N,N-2-yn-1-amine were synthesized and evaluated against Aurora-A kinase.The most potent derivatives were 6a and 6k with IC 50 values 36.6 and 38.8 μM, respectively. Docking studies probed the binding interactions of these compounds within the active site of the kinase. The ndings contribute to the development of novel cancer therapeutics and offer promise for more effective and targeted treatments in the future.

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Discovery and Synthesis of a Pyrimidine-Based Aurora Kinase Inhibitor to Reduce Levels of MYC Oncoproteins

Cited by 10 publications

References 44 publications

Molecular classification of small cell lung cancer subtypes: Characteristics, prognostic factors, and clinical translation

Molecular classification of small cell lung cancer subtypes: Characteristics, prognostic factors, and clinical translation

Synthetic Strategies of Pyrimidine-Based Scaffolds as Aurora Kinase and Polo-like Kinase Inhibitors

Synthesis, anticancer evaluation and docking studies of novel adamantanyl-1,3,4-oxadiazol hybrid compounds as Aurora-A kinase inhibitors

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