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Mol Cancer Ther. 2017 Nov;16(11):2375-2386. doi: 10.1158/1535-7163.MCT-17-0233. Epub 2017 Sep 6.

The p97 Inhibitor CB-5083 Is a Unique Disrupter of Protein Homeostasis in Models of Multiple Myeloma.

Author information

1
Cleave Biosciences, Inc., Burlingame, California. ronan.lemoigne29@gmail.com.
2
Department of Medicine, Division of Hematology & Oncology, University of California San Francisco, San Francisco, California.
3
Cleave Biosciences, Inc., Burlingame, California.
4
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
5
Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California.
6
Comprehensive Cancer Center, Mayo Clinic, Scottsdale, Arizona.
7
Experimental Oncology and Hematology, Department of Oncology and Hematology, St. Gallen, Switzerland.

Abstract

Inhibition of the AAA ATPase, p97, was recently shown to be a novel method for targeting the ubiquitin proteasome system, and CB-5083, a first-in-class inhibitor of p97, has demonstrated broad antitumor activity in a range of both hematologic and solid tumor models. Here, we show that CB-5083 has robust activity against multiple myeloma cell lines and a number of in vivo multiple myeloma models. Treatment with CB-5083 is associated with accumulation of ubiquitinated proteins, induction of the unfolded protein response, and apoptosis. CB-5083 decreases viability in multiple myeloma cell lines and patient-derived multiple myeloma cells, including those with background proteasome inhibitor (PI) resistance. CB-5083 has a unique mechanism of action that combines well with PIs, which is likely owing to the p97-dependent retro-translocation of the transcription factor, Nrf1, which transcribes proteasome subunit genes following exposure to a PI. In vivo studies using clinically relevant multiple myeloma models demonstrate that single-agent CB-5083 inhibits tumor growth and combines well with multiple myeloma standard-of-care agents. Our preclinical data demonstrate the efficacy of CB-5083 in several multiple myeloma disease models and provide the rationale for clinical evaluation as monotherapy and in combination in multiple myeloma. Mol Cancer Ther; 16(11); 2375-86. ©2017 AACR.

PMID:
28878026
DOI:
10.1158/1535-7163.MCT-17-0233
[Indexed for MEDLINE]
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