Wednesday, February 5, 2025
2/5/2025
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 β5 and tryptic β2 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 β5 to cleave after hydrophobic residues and the “tryptic” preference of β2 to cleave after basic residues, it is challenging to develop inhibitors that can target both β2 and β5 with similar potency. Besides, such β5β2 targeting inhibitors would also have to spare the “acidic” β1 active subunit to avoid nonspecific cytotoxicity. No such inhibitors have been reported in peptide boronate and peptide epoxyketone classes. There are three known β5β2-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 β5 and β2, but not β1. 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 β5β2 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 β5β2-inhibitors’ potency, specificity and pharmacokinetic properties. In Aim 2, we will test β5β2- inhibitors' cytotoxicity against breast cancer line cells. Aim 3 will test the efficacy of β5β2-inhibitors in in animal models of TNBC.
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