Wednesday, May 8, 2024
5/8/2024
Project Summary/Abstract Proteasome inhibitor (PI) drugs turned untreatable multiple myeloma treatable, significantly improve the quality of life for multiple myeloma patients. There are three FDA-approved PI drugs. In additional to multiple myeloma (MM), PI drugs are also approved to treat mantle cell lymphoma (MCL), amyloid light chain (AL) amyloidosis and Waldenström macroglobulinemia, the latter two are noncurable rare disorders related to plasma cells. Nevertheless, resistance inevitably occurs. All three drugs have serious toxicities. A high percentage of patients suffer from neuropathy, a debilitating adverse effect from two peptide boronate based PI drugs, bortezomib and ixazomib. Another PI drug carfilzomib also has cardiovascular and renal toxicity. Notably, none of the PI drugs showed little clinical benefits in treating patients with solid tumors in numerous clinical trials. Studies have shown that upon treatment with PIs, a transcription factor NRF1 will be activated to express more proteasomes that renders PI drugs less or non-effective. Recent studies show that when chymotryptic ß5 and tryptic ß2 of the proteasomes are simultaneously inhibited, NRF1, instead of activation, forms aggregated, disarming the ability of tumor cells to resist apoptotic stress induced from proteasome inhibition. Because of the striking difference between the “chymotryptic” proteolytic preference of ß5 to cleave after hydrophobic residues and the “tryptic” preference of ß2 to cleave after basic residues, it is challenging to develop inhibitors that can target both ß2 and ß5 with similar potency. Besides, such ß5ß2 targeting inhibitors would also have to spare the “acidic” ß1 active subunit to avoid nonspecific cytotoxicity. No such inhibitors have been reported in peptide boronate and peptide epoxyketone classes. There are three known ß5ß2-inhibitors in other classes, all of them irreversible, carrying unpredictable toxicities. We have now designed and characterized a group of macrocyclic peptide boronates that simultaneously inhibit ß5 and ß2, but not ß1. These compounds elicit markedly less NRF1 activation in triple negative breast cancer cells (TNBC) than BTZ. We now aim to continue our team approach to advance the structure-guided development of ß5ß2 inhibitors for cancer treatment by improving their specificity and pharmaceutical properties and evaluate their in vitro anticancer activity and in vivo efficacy in animal models of TNBC. In Aim 1 of this proposal, we will conduct structure-guided lead optimization to improve ß5ß2-inhibitors’ potency, specificity and pharmacokinetic properties. In Aim 2, we will test ß5ß2- inhibitors' cytotoxicity against breast cancer line cells. Aim 3 will test the efficacy of ß5ß2-inhibitors in in animal models of TNBC.
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