المؤلفون: LaMonte, Gregory M, Almaliti, Jehad, Bibo-Verdugo, Betsaida, Keller, Lena, Zou, Bing Yu, Yang, Jennifer, Antonova-Koch, Yevgeniya, Orjuela-Sanchez, Pamela, Boyle, Colleen A, Vigil, Edgar, Wang, Lawrence, Goldgof, Gregory M, Gerwick, Lena, O’Donoghue, Anthony J, Winzeler, Elizabeth A, Gerwick, William H, Ottilie, Sabine

المصدر: Journal of Medicinal Chemistry. 60(15)

مصطلحات موضوعية: Biotechnology, Rare Diseases, Orphan Drug, Vector-Borne Diseases, Infectious Diseases, Malaria, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Infection, Good Health and Well Being, Antimalarials, Artemisinins, Dipeptides, Drug Design, Enzyme Assays, Hep G2 Cells, Humans, Molecular Docking Simulation, Oligopeptides, Plasmodium falciparum, Proteasome Endopeptidase Complex, Proteasome Inhibitors, Saccharomyces cerevisiae, Medicinal and Biomolecular Chemistry, Organic Chemistry, Pharmacology and Pharmaceutical Sciences, Medicinal & Biomolecular Chemistry

الوصف: Naturally derived chemical compounds are the foundation of much of our pharmacopeia, especially in antiproliferative and anti-infective drug classes. Here, we report that a naturally derived molecule called carmaphycin B is a potent inhibitor against both the asexual and sexual blood stages of malaria infection. Using a combination of in silico molecular docking and in vitro directed evolution in a well-characterized drug-sensitive yeast model, we determined that these compounds target the β5 subunit of the proteasome. These studies were validated using in vitro inhibition assays with proteasomes isolated from Plasmodium falciparum. As carmaphycin B is toxic to mammalian cells, we synthesized a series of chemical analogs that reduce host cell toxicity while maintaining blood-stage and gametocytocidal antimalarial activity and proteasome inhibition. This study describes a promising new class of antimalarial compound based on the carmaphycin B scaffold, as well as several chemical structural features that serve to enhance antimalarial specificity.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/0r57k1b0Test

المؤلفون: Fu, Liqiang, Zhang, Jing, Shen, Bin, Kong, Linglong, Liu, Yingtao, Tu, Wangyang, Wang, Wenqian, Cai, Xin, Wang, Xiaotao, Cheng, Na, Xia, Mingxuan, Zhou, Tianyuan, Liu, Qian, Xu, Yanping, Yang, Jennifer, Gavine, Paul, Philippar, Ulrike, Attar, Ricardo, Edwards, James P., Venable, Jennifer D., Dai, Xuedong

المصدر: Journal of Medicinal Chemistry; 20210101, Issue: Preprints

مستخلص: MyD88 gene mutation has been identified as one of the most prevalent driver mutations in the activated B-cell-like diffuse large B-cell lymphoma (ABC DLBCL). The published literature suggests that interleukin-1 receptor-associated kinase 1 (IRAK1) is an essential gene for ABC DLBCL harboring MyD88 mutation. Importantly, the scaffolding function of IRAK1, rather than its kinase activity, is required for tumor cell survival. Herein, we present our design, synthesis, and biological evaluation of a novel series of potent and selective IRAK1 degraders. One of the most potent compounds, Degrader-3(JNJ-1013), effectively degraded cellular IRAK1 protein with a DC50of 3 nM in HBL-1 cells. Furthermore, JNJ-1013potently inhibited IRAK1 downstream signaling pathways and demonstrated strong anti-proliferative effects in ABC DLBCL cells with MyD88 mutation. This work suggests that IRAK1 degraders have the potential for treating cancers that are dependent on the IRAK1 scaffolding function.