Novel Protein Disulfide Isomerase Inhibitor with Anticancer Activity in Multiple Myeloma
Autor: | Yvonne Parker, Jennifer C Hu, Dale Grabowski, Claudiu V. Cotta, Sujatha Chilakala, James G. Phillips, Fei Zhong, Shravya Govindgari, Rebecca R Kuang, Daniel J. Lindner, Yan Xu, Babal K. Jha, Samantha Tall, Sergei Vatolin, Mitchell R. Smith, Frederic J. Reu, Clark W. Distelhorst |
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Rok vydání: | 2016 |
Předmět: |
0301 basic medicine
Cancer Research Protein Conformation Blotting Western Protein Disulfide-Isomerases Antineoplastic Agents Apoptosis Biology Endoplasmic Reticulum Mice 03 medical and health sciences 0302 clinical medicine In vivo Tumor Cells Cultured medicine Animals Humans Enzyme Inhibitors Protein disulfide-isomerase Multiple myeloma Cell Proliferation Binding Sites Cell growth Bortezomib Endoplasmic reticulum Thiones Endoplasmic Reticulum Stress medicine.disease Xenograft Model Antitumor Assays Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure Oncology Biochemistry 030220 oncology & carcinogenesis Cancer research Unfolded protein response Thiazolidines Bone marrow Multiple Myeloma Oxidation-Reduction medicine.drug |
Zdroj: | Cancer Research. 76:3340-3350 |
ISSN: | 1538-7445 0008-5472 |
Popis: | Multiple myeloma cells secrete more disulfide bond–rich proteins than any other mammalian cell. Thus, inhibition of protein disulfide isomerases (PDI) required for protein folding in the endoplasmic reticulum (ER) should increase ER stress beyond repair in this incurable cancer. Here, we report the mechanistically unbiased discovery of a novel PDI-inhibiting compound with antimyeloma activity. We screened a 30,355 small-molecule library using a multilayered multiple myeloma cell–based cytotoxicity assay that modeled disease niche, normal liver, kidney, and bone marrow. CCF642, a bone marrow–sparing compound, exhibited a submicromolar IC50 in 10 of 10 multiple myeloma cell lines. An active biotinylated analog of CCF642 defined binding to the PDI isoenzymes A1, A3, and A4 in MM cells. In vitro, CCF642 inhibited PDI reductase activity about 100-fold more potently than the structurally distinct established inhibitors PACMA 31 and LOC14. Computational modeling suggested a novel covalent binding mode in active-site CGHCK motifs. Remarkably, without any further chemistry optimization, CCF642 displayed potent efficacy in an aggressive syngeneic mouse model of multiple myeloma and prolonged the lifespan of C57BL/KaLwRij mice engrafted with 5TGM1-luc myeloma, an effect comparable to the first-line multiple myeloma therapeutic bortezomib. Consistent with PDI inhibition, CCF642 caused acute ER stress in multiple myeloma cells accompanied by apoptosis-inducing calcium release. Overall, our results provide an illustration of the utility of simple in vivo simulations as part of a drug discovery effort, along with a sound preclinical rationale to develop a new small-molecule therapeutic to treat multiple myeloma. Cancer Res; 76(11); 3340–50. ©2016 AACR. |
Databáze: | OpenAIRE |
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