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Published on: December 13, 2018
Novel Protein Disulfide Isomerase Inhibitor with Anticancer Activity in Multiple Myeloma
Sergei Vatolin1, James G Phillips1, Babal K Jha1
1Department of Translational Hematology & Oncology Research, Cleveland Clinic, Cleveland, Ohio.
Abstract:
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.
Insights
Researchers discovered CCF642, a novel compound that inhibits protein disulfide isomerases (PDI) to treat multiple myeloma. This bone marrow-sparing drug effectively reduced cancer cells and prolonged survival in preclinical models.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Multiple myeloma cells produce high levels of disulfide bond-rich proteins, making them vulnerable to endoplasmic reticulum (ER) stress.
- Inhibiting protein disulfide isomerases (PDIs), crucial for protein folding in the ER, presents a potential therapeutic strategy for multiple myeloma.
Purpose of the Study:
- To discover novel small-molecule inhibitors of PDIs with antimyeloma activity.
- To evaluate the efficacy and safety of a newly identified compound, CCF642, in preclinical models of multiple myeloma.
Main Methods:
- Screening of a 30,355-compound library using a cytotoxicity assay simulating the multiple myeloma disease niche.
- Biochemical assays to determine PDI isoenzyme binding and inhibitory activity of CCF642.
- In vivo efficacy studies in a syngeneic mouse model of multiple myeloma.
Main Results:
- CCF642 demonstrated potent cytotoxicity against multiple myeloma cell lines with a submicromolar IC50 and spared bone marrow cells.
- CCF642 selectively binds to PDI isoenzymes A1, A3, and A4 and inhibits PDI reductase activity significantly more than existing inhibitors.
- CCF642 showed potent efficacy in a mouse model, prolonging survival comparably to bortezomib, and induced ER stress and apoptosis in myeloma cells.
Conclusions:
- CCF642 is a novel, potent, and bone marrow-sparing PDI inhibitor with significant preclinical antimyeloma activity.
- The study validates the use of in vivo simulations in drug discovery and supports the development of CCF642 as a new therapeutic for multiple myeloma.
