Journal article

Marizomib irreversibly inhibits proteasome to overcome compensatory hyperactivation in multiple myeloma and solid tumour patients

Nancy Levin, Andrew Spencer, Simon J Harrison, Dharminder Chauhan, Francis J Burrows, Kenneth C Anderson, Steven D Reich, Paul G Richardson, Mohit Trikha

British Journal of Haematology | WILEY | Published : 2016


Proteasome inhibitors (PIs) are highly active in multiple myeloma (MM) but resistance is commonly observed. All clinical stage PIs effectively inhibit chymotrypsin-like (CT-L) activity; one possible mechanism of resistance is compensatory hyperactivation of caspase-like (C-L) and trypsin-like (T-L) subunits, in response to CT-L blockade. Marizomib (MRZ), an irreversible PI that potently inhibits all three 20S proteasome subunits with a specificity distinct from other PIs, is currently in development for treatment of MM and malignant glioma. The pan-proteasome pharmacodynamic activity in packed whole blood and peripheral blood mononuclear cells was measured in two studies in patients with adv..

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Funding Acknowledgements

Levin: Employee of Triphase Accelerator Corp. Spencer: Celgene Corporation, Honoraria and Research Funding. Harrison: No disclosures. Chauhan: Consultant for Triphase Accelerator Corp. Burrows: Consultant for Triphase Accelerator Corp. Anderson: Bristol-Myers Squibb Pharmaceuticals, Celgene Corporation, Gilead Pharmaceuticals, Millenium (The Takeda Oncology Company): Advisor Board. Acetylon Pharmaceutcials, OncoPep, Inc: Scientific Founder. Reich: Consultant for Triphase Accelerator Corp. Richardson: Celgene and Millenium (The Takeda Oncology Company); Service on Advisory Committees, Research Funding. Trikha: Employee of Triphase Accelerator Corp.