The PI3K/AKT/mTOR pathway is one of the most common dysregulated signaling cascade responses in human cancers, playing a crucial role in cell proliferation and angiogenesis. Therefore, the development of anticancer drugs targeting the PI3K and mTOR pathways has become a research hotspot in cancer treatment. In this study, the PI3K selective inhibitor GDC-0941 was selected as a lead compound, and 28 thiophenyl-triazine derivatives with aromatic urea structures were synthesized based on scaffold hopping, serving as a novel class of PI3K/mTOR dual inhibitors. The most promising compound Y-2 was obtained through antiproliferative activity evaluation, kinase inhibition, and toxicity assays. The results showed that Y-2 demonstrated potential inhibitory effects on both PI3K kinase and mTOR kinase, with IC values of 171.4 and 10.2 nM, respectively. The inhibitory effect of Y-2 on mTOR kinase was 52 times greater than that of the positive drug GDC-0941. Subsequently, the antitumor activity of Y-2 was verified through pharmacological experiments such as AO staining, cell apoptosis, scratch assays, and cell colony formation. The antitumor mechanism of Y-2 was further investigated through JC-1 experiments, real-time quantitative PCR, and Western blot analysis. Based on the above experiments, Y-2 can be identified as a potent PI3K/mTOR dual inhibitor for cancer treatment.
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http://dx.doi.org/10.1002/ardp.202300403 | DOI Listing |
ACS Pharmacol Transl Sci
December 2024
Amity Institute of Integrative Sciences and Health, Amity University Haryana, Panchgaon, Manesar, Gurgaon-122413, Haryana, India.
The mechanistic target of rapamycin kinase (MTOR) is pivotal for cell growth, metabolism, and survival. It functions through two distinct complexes, mechanistic TORC1 and mechanistic TORC2 (mTORC1 and mTORC2). These complexes function in the development and progression of cancer by regulating different cellular processes, such as protein synthesis, lipid metabolism, and glucose homeostasis.
View Article and Find Full Text PDFBiomedicines
October 2024
College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA.
: () is a pathogen that causes tuberculosis (TB), an extremely infectious disease which is responsible for millions of deaths worldwide. The severity of this pathogen is further amplified with the emergence of multidrug-resistant strains that are becoming more prevalent at an alarming rate, and novel treatments are needed. : In this paper, we discuss the pathology infection.
View Article and Find Full Text PDFJ Org Chem
November 2024
School of Radiology, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, Shandong 271016, China.
The efficient synthesis of the pyrrolo[4,3,2-]quinoline core of the lymphostin family (compound ) has been accomplished in 7 steps and 18.6% overall yield, providing an efficient method for the total synthesis and structural modification of the lymphostin family. Compound showed potent inhibitory activities against PI3K/mTOR in the nanomolar range and activity against human colorectal cancer cell lines comparable to that of oxaliplatin, which could be recognized as a novel lead compound for cancer therapy.
View Article and Find Full Text PDFArch Pharm (Weinheim)
November 2024
Fatimah College of Health Sciences, Al Ain, United Arab Emirates.
Cancer ranks among the most life-threatening diseases worldwide and is continuously affecting all age groups. Consequently, many research studies are being carried out to develop new cancer treatments, but many of them experience resistance and cause severe toxicity to the patients. Therefore, there is a continuous need to design novel anticancer agents that are target-based, have a higher potency, and have minimal toxicity.
View Article and Find Full Text PDFMol Oncol
August 2024
Celcuity, Inc., Minneapolis, MN, USA.
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