Track topics on Twitter Track topics that are important to you
Over the past 15 years, proteasome inhibitors (PIs), namely bortezomib, carfilzomib (Cfz) and ixazomib, have significantly improved the overall survival and quality-of-life for multiple myeloma (MM) patients. However, a significant portion of MM patients do not respond to PI therapies. Drug resistance is present either de novo or acquired after prolonged therapy through mechanisms that remain poorly defined. The lack of a clear understanding of clinical PI resistance has hampered the development of next-generation PI drugs to treat MM patients who no longer respond to currently-available therapies. Here, we designed and synthesized novel epoxyketone-based PIs by structural modifications at the P1' site. We show that a Cfz analog, 9, harboring a hydroxyl substituent at its P1' position was highly cytotoxic against cancer cell lines displaying de novo or acquired resistance to Cfz. These results suggest that peptide epoxyketones incorporating P1'-targeting moieties may have the potential to bypass resistance mechanisms associated with Cfz and to provide additional clinical options for patients resistant to Cfz.
This article was published in the following journal.
Name: Journal of medicinal chemistry
Macrocyclization has been frequently utilized for optimizing peptide or peptidomimetic-based compounds. In an attempt to obtain potent, metabolically stable, and orally available proteasome inhibitors...
Multiple myeloma (MM) is a cancer of plasma cells, characterized by abundant synthesis of monoclonal immunoglobulins and/or free light chains. Although MM remains incurable, median overall survival ha...
As proteasome inhibitors, a series of novel macrocyclic dipeptide N-benzyl amides were designed, synthesized and evaluated. Most of them exhibited potent proteasome inhibition and excellent anti-proli...
Subunit-selective proteasome inhibitors are valuable tools to assess the biological function and medicinal relevance of individual proteasome active sites in a specific context. While inhibitors for t...
Proteasomal system plays an important role in maintaining cell homeostatis. Overexpression of proteasomes leads to several major diseases, such as cancer and autoimmune disorder. The β5 subunit of pr...
Trial objectives: To decide whether the addition of nelfinavir to the approved antimyeloma therapy with bortezomib and dexamethasone has sufficient activity in proteasome inhibitor-resist...
All patients with multiple myeloma (MM) are destined to relapse even with the best available approved agents. Median OS from diagnosis in the current era is reported at 5.4 years. Given th...
This study will evaluate the usefulness of plasma proteasome levels as a tumor marker of hepatocellular carcinoma (HCC) by studying their variation following curative treatment of HCC. The...
Velcade (bortezomib, PS-341) has recently been approved by the Food and Drug Administration (FDA) for the treatment of multiple myeloma (MM) for patients who have received at least one pri...
A Study to Evaluate the Efficacy and Safety of Ixazomib in Combination With Lenalidomide and Dexamethasone in Patients With Relapsed and/or Refractory Multiple Myeloma Initially Treated With an Injection of Proteasome Inhibitor-Based Therapy
The purpose of this study is to investigate the efficacy and safety of long-term administration of the oral proteasome inhibitor ixazomib as part of ixazomib in combination with lenalidomi...
Compounds that inhibit the function or proteolytic action of the PROTEASOME.
Teaching strategy of shared learning based cross-discipline experiences and placements.
A strategy for purchasing health care in a manner which will obtain maximum value for the price for the purchasers of the health care and the recipients. The concept was developed primarily by Alain Enthoven of Stanford University and promulgated by the Jackson Hole Group. The strategy depends on sponsors for groups of the population to be insured. The sponsor, in some cases a health alliance, acts as an intermediary between the group and competing provider groups (accountable health plans). The competition is price-based among annual premiums for a defined, standardized benefit package. (From Slee and Slee, Health Care Reform Terms, 1993)
Agents and endogenous substances that antagonize or inhibit the development of new blood vessels.
Disorders in which there is a delay in development based on that expected for a given age level or stage of development. These impairments or disabilities originate before age 18, may be expected to continue indefinitely, and constitute a substantial impairment. Biological and nonbiological factors are involved in these disorders. (From American Psychiatric Glossary, 6th ed)
Cancer is not just one disease but many diseases. There are more than 100 different types of cancer. Most cancers are named for the organ or type of cell in which they start - for example, cancer that begins in the colon is called colon cancer; cancer th...
Pharmacy is the science and technique of preparing as well as dispensing drugs and medicines. It is a health profession that links health sciences with chemical sciences and aims to ensure the safe and effective use of pharmaceutical drugs. The scope of...