Grants and Contracts Details
The long-term goals of this project are to develop a next-generation proteasome inhibitor that will provide a new therapeutic option 1) for multiple myeloma (MM) patients refractory to bortezomib or carfilzomib as well as 2) for patients with solid cancers. The FDA approval of bortezomib (Velcade®), the first-in-class proteasome inhibitor, in 2003 for the treatment of MM patients validated the proteasome as an anticancer target. In 2012, the second-generation proteasome inhibitor carfilzomib (Kyprolis®) was approved by the FDA for the treatment of relapsed MM patients who have received at least two prior therapies, including bortezomib. The addition of these proteasome inhibitors to chemotherapeutic weapons has dramatically improved the therapeutic landscape for patients with multiple myeloma (MM). Despite these exciting advancements, intrinsic and acquired drug resistance remains a major clinical challenge. Additionally, these drugs have failed to provide clinical benefit to patients with solid cancers, even though they displayed promising anticancer activities in preclinical animal models of solid cancers. Thus, there is still much work to be done to provide next-generation proteasome inhibitors which overcome intrinsic and acquired drug resistance and which have clinical utility outside of MM. With this in mind, we hypothesize that a new class of proteasome inhibitors with non-peptide scaffolds will provide new therapeutic options for MM patients refractory to bortezomib or carfilzomib and those with solid cancers. This is based on the fact that bortezomib, carfilzomib, and nearly all proteasome inhibitors under clinical and preclinical development share common structural features of peptide backbones and reactive pharmacophores. These features are known to render the drugs less stable in vivo, more susceptible to off-target interactions and cross-resistance. Therefore, we propose to develop non-peptide compounds that inhibit the proteasome via novel binding modes and provide better pharmacokinetics profiles. In our preliminary work, using a virtual screen and following in vitro enzyme kinetics, we identified several promising hits with diverse non-peptide scaffolds and inhibitory activities against the proteasome. One compound, a tri-substituted pyrazole derivative, appeared especially promising, and the synthesis and evaluation of a number of analogs of this compound led to the discovery of G4-1, our current lead candidate. G4-1 displayed anticancer activity in various cell lines and its efficacy was not negatively impacted by acquired or intrinsic resistance to bortezomib or carfilzomib. Compared with carfilzomib and bortezomib, G4-1 showed excellent in vitro metabolic stability. Furthermore, G4-1 was highly effective in suppressing tumor growth with no apparent toxicity in vivo. Following up on these exciting findings, we propose: 1) to expand our lead optimization efforts in order to develop potent proteasome inhibitors with improved in vivo stability and pharmacokinetic profiles, 2) to investigate the in vitro efficacy and molecular mechanism underlying anticancer effects of 1-2 selected compounds, and 3) to evaluate the efficacy and PK properties of novel proteasome inhibitors in vivo for translational development as novel agents for the treatment of cancer patients. In summary, we expect that a non-peptide proteasome inhibitors developed in this application will overcome drawbacks of the existing proteasome-targeting drugs and expand clinical benefits to more patients with MM and potentially to those with solid cancers.
|Effective start/end date||7/7/14 → 5/31/20|
- National Cancer Institute: $1,510,194.00
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