Xu, Xi published the artcileStructure-Enabled Discovery of Novel Macrocyclic Inhibitors Targeting Glutaminase 1 Allosteric Binding Site, SDS of cas: 621-37-4, the publication is Journal of Medicinal Chemistry (2021), 64(8), 4588-4611, database is CAplus and MEDLINE.
The inhibition of glutaminase 1 (GLS1) represents a potential treatment of malignant tumors. Structural anal. led to the design of a novel series of macrocyclic GLS1 allosteric inhibitors. Through extensive structure-activity relationship studies, a promising candidate mol. 13b (LL202) was identified with robust GLS1 inhibitory activity (IC50 = 6 nM) and high GLS1 binding affinity (SPR, Kd = 24 nM; ITC, Kd = 37 nM). The X-ray crystal structure of the 13b-GLS1 complex was resolved, revealing a unique binding mode and providing a novel structural scaffold for GLS1 allosteric inhibitors. Importantly, 13b clearly adjusted the cellular metabolites and induced an increase in the ROS level by blocking glutamine metabolism Furthermore, 13b exhibited a similar in vivo antitumor activity as CB839. This study adds to the growing body of evidence that macrocyclization provides an alternative and complementary approach for the design of small-mol. inhibitors, with the potential to improve the binding affinity to the targets.
Journal of Medicinal Chemistry published new progress about 621-37-4. 621-37-4 belongs to alcohols-buliding-blocks, auxiliary class Carboxylic acid,Benzene,Phenol,Natural product, name is 3-Hydroxyphenylacetic acid, and the molecular formula is C20H17FO4S, SDS of cas: 621-37-4.
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