Discovery of 4-(4-(3-(1-(2-(piperidin-1-yl)ethyl)-1H-benzo[d]imidazole-2-yl)isoxazol-5-yl)phenyl)morpholine as a novel c-Myc inhibitor against lung cancer in vitro and in vivo

Article

Author: Jia, Pingting ; Zhao, Hui ; Zhang, Zihui ; Chen, Jiahui ; Hong, Renjie ; Yin, Jiacheng ; Li, Mengting ; Gao, Jian ; Li, Shihao ; Qu, Xinxin

The critical role of c-Myc as a driving factor in the development and progression of lung cancer establishes it as a pivotal target for anti-lung cancer therapeutic research. In our previous study, we reported on the discovery of D347-2761, a novel small-molecule inhibitor that specifically targets the unstable domain of c-Myc and disrupts the c-Myc/Max heterodimer. To enhance targeted therapies further, we conducted an extensive structural analysis and designed a series of innovative benzimidazole derivatives. The cytotoxic activities of these compounds were assessed using the CCK-8 assay, revealing that compound A1 displayed IC₅₀ values of 6.32 μM and 11.39 μM against the A549 and NCI-H1299 lung cancer cell lines, respectively, while compound A5 exhibited IC₅₀ values of 4.08 μM and 7.86 μM against the same cell lines. Our findings revealed that compounds A1 and A5 exhibited potent anticancer activity by disrupting the interaction between c-Myc and Max proteins, leading to the downregulation of c-Myc protein levels and induction of apoptosis through apoptotic pathways. Notably, compound A5 demonstrated superior inhibitory capacity compared to other compounds tested. Furthermore, in a syngeneic tumor model, compound A5 exhibited excellent efficacy with a tumor growth inhibition rate reaching up to 76.4 %, accompanied by a significant reduction in c-Myc protein expression levels. Therefore, compound A5 holds promise as a potential agent for targeting c-Myc in anti-lung cancer therapy.

01 Dec 2024·Bioorganic Chemistry

Identification of sanguinarine as c-MYC transcription inhibitor through enhancing the G-quadruplex-NM23-H2 interactions

Article

Author: Zhang, Zi-Lin ; Tan, Jia-Heng ; Zhong, Li-Ting ; Li, Xiaoya ; Chen, Shuo-Bin ; Fu, Wen-Li ; Huang, Zhi-Shu ; Yuan, Jing-Mei ; Ou, Tian-Miao

c-MYC is a proto-oncogene ubiquitously overexpressed in various cancers. The formation of G-quadruplex (G4) structures within the c-MYC promoter region can regulate its transcription by interfering with protein binding. Consequently, small molecules targeting c-MYC G4 have emerged as promising anticancer agents. Herein, we report that sanguinarine (SG) and its analogs exhibit a high affinity for c-MYC G4 and potently modulate G4-protein interactions within a natural product library. Notably, SG uniquely enhances NM23-H2 binding to c-MYC G4, both in vitro and in cellular contexts, leading to c-MYC transcriptional repression and subsequent inhibition of cancer cell growth in an NM23-H2-dependent manner. Mechanistic studies and molecular modeling suggest that SG binds to the c-MYC G4/NM23-H2 interface, acting as an orthosteric stabilizer of the DNA-protein complex and preventing c-MYC transcription. Our findings identify SG as a potent c-MYC transcription inhibitor and provide a novel strategy for developing G4-targeting anticancer therapeutics through modulation of G4-protein interactions.

01 May 2024·Biomedicine & Pharmacotherapy

A novel combined therapeutic strategy of Nano-EN-IR@Lip mediated photothermal therapy and stem cell inhibition for gastric cancer

Article

Author: Liu, Yadong ; Liao, Fangli ; Wang, Can ; Zhan, Zhu ; Du, Yan-E ; Wang, Zhigang ; Huang, Tong ; Liu, Junzhao ; Cao, Yang ; Yang, Liping ; Chen, Weixian

Recurrence and metastasis of gastric cancer is a major therapeutic challenge for treatment. The presence of cancer stem cells (CSCs) is a major obstacle to the success of current cancer therapy, often leading to treatment resistance and tumor recurrence and metastasis. Therefore, it is important to develop effective strategies to eradicate CSCs. In this study, we developed a combined therapeutic strategy of photothermal therapy (PTT) and gastric cancer stem cells (GCSCs) inhibition by successfully synthesizing nanoliposomes loaded with IR780 (photosensitizer) and EN4 (c-Myc inhibitor). The nanocomposites are biocompatible and exhibit superior photoacoustic (PA) imaging properties. Under laser irradiation, IR780-mediated PTT effectively and rapidly killed tumor cells, while EN4 synergistically inhibited the self-renewal and stemness of GCSCs by suppressing the expression and activity of the pluripotent transcription factor c-Myc, preventing the tumor progression of gastric cancer. This Nano-EN-IR@Lip is expected to be a novel clinical nanomedicine for the integration of gastric cancer diagnosis, treatment and prevention.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	US	Ribometrix, Inc.Startup	02 Apr 2024

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