Marizomib (Proteasome Inhibitor)

Proposed Mechanism of Action

Marizomib is a proteasome inhibitor derived from a novel marine-obligate actinomycete that belongs to the β-lactone-γ-lactam superfamily of proteasome inhibitors.1 In in vitro experiments, marizomib has demonstrated irreversible binding to and inhibition of all 3 proteolytic subunits of the human proteasome complex, resulting in inhibition of proteasome activity.2,3

Marizomib by Disease State

Marizomib in Glioma

Rationale for Clinical Development

In vitro experiments have revealed that marizomib inhibited proliferation and invasion and induced apoptosis in glioma cells.4 In addition, studies in rats demonstrated distribution of marizomib into the brain, and studies in monkeys demonstrated inhibition of chymotrypsin-like proteasome activity in brain tissues.4

Marizomib in Multiple Myeloma

Rationale for Clinical Development

In preclinical studies, marizomib has exhibited high specificity for the proteasome and has been shown in vitro to inhibit proteasomes induced by cytokines, which are predominantly found in cells of hematopoietic origin, including multiple myeloma (MM) cells.5,6

Resistance to and toxicity with bortezomib therapy in patients with MM have led to the search for alternative proteasome inhibitors with the potential to treat patients who had experienced failure with, did not respond to, or were not candidates for treatment with bortezomib.7,8 In preclinical studies, marizomib has demonstrated a broad proteasome inhibition profile.9

The safety and efficacy of the agents and/or uses under investigation have not been established. There is no guarantee that the agents will receive health authority approval or become commercially available in any country for the uses being investigated.

Celgene acquired this asset from Triphase in 2016. Triphase continues to support marizomib’s development by remaining involved with the ongoing clinical trials.

References

  1. Feling RH, et al. Angew Chem Int Ed Engl. 2003;42:355-357.
  2. Groll M, et al. J Am Chem Soc. 2006;128:5136-5141.
  3. Chao T-H, et al. 100th Annual AACR Meeting [abstract 4539].
  4. Di K, et al. Neuro Oncol. 2016;18:840-848.
  5. Potts BC, et al. Curr Cancer Drug Targets. 2011;11:254-284.
  6. Parlati F, et al. Blood. 2009;114:3439-3447.
  7. Richardson PG, et al. J Clin Oncol. 2006;24:3113-3120.
  8. Lonial S, et al. Blood. 2005;106:3777-3784.
  9. Chauhan D, et al. Cancer Cell. 2005;8:407-419.