Preliminary work indicates the mTOR-binding protein DEPTOR is a potential molecular target for therapy in multiple myeloma. It is specifically upregulated in this disease and its silencing is lethal to myeloma cells. We, thus, identified a potential DEPTOR inhibitor in a high-throughput drug screen. The inhibitor is effective in myeloma cells with the expected molecular alterations and induction of death. In this proposal we plan to further develop this inhibitor. We will generate biochemical derivatives with the aim of enhancing the therapeutic index of DEPTOR inhibitors, identify the mechanism of action of where the inhibitors first bind in myeloma cells, ascertain possible toxicity to normal tissues in mice with deleted DEPTOR expression and assess possible interactions with other anti-myeloma therapeutics that are used in the clinic. Our expectation is that these new drugs will be important additions to the armamentarium used in myeloma patients and, furthermore, they will be specifically tailored to patients with tumors that have high DEPTOR expression.
This proposal designs a plan to develop DEPTOR inhibitors for future use in the clinic for patients with multiple myeloma. Multiple myeloma is a frequently diagnosed malignancy in the US and is currently incurable. Thus, we believe our proposal may be able to provide newer treatments to be added to the armamentarium to be used against this serious disease.
| Lee, Jihye; Shi, Yijiang; Vega, Mario et al. (2017) Structure-activity relationship study of small molecule inhibitors of the DEPTOR-mTOR interaction. Bioorg Med Chem Lett 27:4714-4724 |
