Evaluation of the Proteasome Inhibitor MLN9708 in Preclinical Models of Human Cancer
| Autor: | Bret Bannerman, Larry Dick, Mark Rolfe, Li Yu, Paul Hales, Jie Yu, Frank J. Bruzzese, Mark Manfredi, Edmund Lee, Michael Fitzgerald, Yueying Cao, Khristofer Garcia, Jane Liu, Joe Bolen, Erik Kupperman, Jonathan L. Blank, Paul E. Fleming, Yu Yang, Christopher Tsu, Allison Berger |
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| Rok vydání: | 2010 |
| Předmět: |
Boron Compounds
Proteasome Endopeptidase Complex Cancer Research Lymphoma Glycine Mice SCID Cysteine Proteinase Inhibitors Pharmacology Ixazomib Bortezomib Mice chemistry.chemical_compound Neoplasms medicine Ixazomib Citrate Animals Humans Multiple myeloma business.industry HCT116 Cells medicine.disease Boronic Acids Xenograft Model Antitumor Assays Oncology chemistry Proteasome Pyrazines Pharmacodynamics Proteasome inhibitor Female Mantle cell lymphoma Drug Screening Assays Antitumor business HT29 Cells Proteasome Inhibitors medicine.drug |
| Zdroj: | Cancer Research. 70:1970-1980 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-09-2766 |
| Popis: | The proteasome was validated as an oncology target following the clinical success of VELCADE (bortezomib) for injection for the treatment of multiple myeloma and recurring mantle cell lymphoma. Consequently, severalgroups are pursuing the development of additional small-molecule proteasome inhibitors for both hematologic and solid tumor indications. Here, we describe MLN9708, a selective, orally bioavailable, second-generation proteasome inhibitor that is in phase I clinical development. MLN9708 has a shorter proteasome dissociation half-life and improved pharmacokinetics, pharmacodynamics, and antitumor activity compared with bortezomib. MLN9708 has a larger blood volume distribution at steady state, and analysis of 20S proteasome inhibition and markers of the unfolded protein response confirmed that MLN9708 has greater pharmacodynamic effects in tissues than bortezomib. MLN9708 showed activity in both solid tumor and hematologic preclinical xenograft models, and we found a correlation between greater pharmacodynamic responses and improved antitumor activity. Moreover, antitumor activity was shown via multiple dosing routes, including oral gavage. Taken together, these data support the clinical development of MLN9708 for both hematologic and solid tumor indications. Cancer Res; 70(5); 1970–80 |
| Databáze: | OpenAIRE |
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