P21-activated kinases (PAKs) are crucial regulators within cellular signaling pathways and have been implicated in a range of human diseases, including cancer. Among the PAK family, PAK2 is widely expressed across various tissues and has emerged as a significant driver of cancer progression. However, systematic studies on PAK2 remain limited. This review provides a comprehensive overview of PAK2's role in cancer, focusing on its involvement in processes such as angiogenesis, metastasis, cell survival, metabolism, immune response, and drug resistance. We also explore its function in key cancer signaling pathways and the potential of small-molecule inhibitors targeting PAK2 for therapeutic purposes. Despite promising preclinical data, no PAK2 inhibitors have reached clinical practice, underscoring challenges related to their specificity and therapeutic application. This review highlights the biological significance of PAK2 in cancer and its interactions with critical signaling pathways, offering valuable insights for future research. We also discuss the major obstacles in developing PAK inhibitors and propose strategies to overcome these barriers, paving the way for their clinical translation.

01 Jan 2025·Biomolecules & Therapeutics

The Dual Role of Survival Genes in Neurons and Cancer Cells: a Strategic Clinical Application of DX2 in Neurodegenerative Diseases and Cancer

Review

Author: Baek, Kyunghwa

In cancer cells, survival genes contribute to uncontrolled growth and the survival of malignant cells, leading to tumor progression. Neurons are post-mitotic cells, fully differentiated and non-dividing after neurogenesis and survival genes are essential for cellular longevity and proper functioning of the nervous system. This review explores recent research findings regarding the role of survival genes, particularly DX2, in degenerative neuronal tissue cells and cancer cells. Survival gene DX2, an exon 2-deleted splice variant of AIMP2 (aminoacyl-tRNA synthetase-interacting multi-functional protein 2), was found to be overexpressed in various cancer types. The potential of DX2 inhibitors as an anti-cancer drug arises from its unique ability to interact with various oncoproteins, such as KRAS and HSP70. Meanwhile, AIMP2 has been reported as a multifunctional cell death-inducing gene, and survival gene DX2 directly and indirectly inhibits AIMP2-induced cell death. DX2 plays multifaceted survival roles in degenerating neurons via various signaling pathways, including PARP 1, TRAF2, and p53 pathways. It is noteworthy that genes that were previously classified as oncogenes, such as AKT and XBP1, are now being considered as curative transgenes for targeting neurodegenerative diseases. A strategic direction for clinical application of survival genes in neurodegenerative disease and in cancer is justified.

13 Dec 2024·ACS Pharmacology & Translational Science

Discovery of 7,9-Dibromo-dihydrodibenzofuran as a Potent Casein Kinase 2 (CK2) Inhibitor: Synthesis, Biological Evaluation, and Structural Studies on E-/Z-Isomers

Article

Author: Schmithals, Claudia ; Niefind, Karsten ; Rumler, Hendrik ; Werner, Christian ; Wünsch, Bernhard ; Bollacke, Andre ; Aichele, Dagmar ; Jose, Joachim ; Götz, Claudia

The human protein kinase CK2 is a promising target for cancer treatment. Only two CK2 inhibitors have reached clinical trials until today. Among others, a dibenzofuran scaffold has emerged as highly prospective for the development of new CK2 inhibitors. Thirty-three newly synthesized dibenzofuran-based compounds were tested on their inhibitory potential in vitro. 7,9-Dichloro-8-hydroxy-4-[(phenylamino)methylene]-1,2-dihydro-dibenzo[b,d]furan-3(4H)-one (12b) and 7,9-dibromo-8-hydroxy-4-[(phenylamino)methylene]-1,2-dihydro-dibenzo[b,d]furan-3(4H)-one (12c) showed the lowest IC₅₀ values with 5.8 nM for both. The dibenzofuran-based CK2 inhibitors crossed the cell membrane of LNCaP human prostate carcinoma cells and reduced intracellular CK2 activity. Among 70 kinases from different representative subgroups of the human kinome, CK2 was most strongly inhibited by compound 12c. Co-crystallization of 12c together with CK2α indicated a π-halogen bond of the bromine at position C9 with the gatekeeper amino acid Phe113. CK2α could bind both the E- and Z-isomers of 12c. Our results provide new insights into the structure-activity relationships of dibenzofuran derivatives.

100 Deals associated with ACE2 inhibitors(University of Chinese Academy of Sciences)

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Indication	Highest Phase	Country/Location	Organization	Date
COVID-19	Preclinical	CN	University of Chinese Academy of Sciences	25 Aug 2021

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ACE2 inhibitors(University of Chinese Academy of Sciences)

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