Neal Green*, Matthew G. LaPorte, William Paquette, Sipak Joyasawal, Pravat Mondal, Zoe Vaughn, Evan J. Carder, Mary Liang, Li Shan, Feng Wang, Francesca Tomaino, Apurva Srivastava, Andrew Flint, William J. Moore, Tsui-Fen Chou, Gordon M. Stott, Mark Wolf, Peter Wipf* and Donna M. Huryn*,
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Antitumor Efficacy of 1,2,4-Triazole-Based VCP/p97 Allosteric Inhibitors
The AAA ATPase p97 (VCP) plays a crucial role in maintaining protein homeostasis through the ubiquitin-proteosome pathway, as well as other mechanisms. Due to the increased mutational load and protein quality control failures in cancer cells, p97 is a potential target for cancer therapy. Here, we highlight the optimization of the previously reported 3-thioalkyl-1,2,4-triazol-pyridyl allosteric inhibitor scaffold and identify two compounds (25 and 38) with low-nanomolar biochemical potency, submicromolar cellular inhibition, in vivo effects on biomarkers of VCP inhibition, and antitumor efficacy in mouse xenograft tumor models. Furthermore, compound 38 demonstrated robust inhibition of VCP ATP-site mutant proteins and growth of cells resistant to the known ATP-competitive inhibitor CB-5083.
期刊介绍：
The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents.
The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.
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