SQSTM1/p62-targeted Small Molecules for Multiple Myeloma Disease

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Despite the introduction of new anti-multiple myeloma (MM) treatment regimens, such as Bortezomib (a top 10 best- selling cancer drug), high MM relapse rates and drug resistance as well as problematic neuropathy and thrombocytopenia side effects continue to plague the current therapies. Furthermore, ~30% MM patients never respond to Bortezomib treatment. Particularly, osteolytic bone diseases and renal failure resulting from hyperparaproteinemia and hypercalcemia have been the major serious sequelae that are inextricably linked with MM tumor progression. So far, MM disease remains the second most common hematological malignancy in the U.S. and incurable with a median survival of 3 to 5 years. Thus, novel MM drug targets and new small-molecule probes are in critical need both to understand the disease-associated pathways and to facilitate anti-MM drug discovery. This Fast Track proposal seeks support for acceleration of FDA IND-enabling preclinical evaluations of the developed high-efficacy/low-toxicity small-molecules, targeting the protein p62 (sequestosome 1, SQSTM1), so called p62ZZ inhibitors. The scientific basis for p62ZZ inhibitors as a novel anti-MM pharmacotherapy includes: i) the innovative discovery of first p62-ZZ antagonist small-molecules, exhibiting significant inhibition of human MM cell growth as reported in our recent publications and patents; ii) the solid experimental confirmation of p62-target specificity, revealing that down regulation or deletion of p62 in marrow stromal cells significantly decreased expression levels of PKCζ, VCAM-1, TNF-α and IL-6, and also decreased the stromal cell support of MM cell growth; iii) the strong experimental verification, showing that ZZ domain of p62 is specifically required for stromal cell support of MM cell growth and osteoclast activation through atypical PKC, NF-κB, MAPK and IL-6 production; iv) the discovered p62-ZZ small-molecule inhibitors demonstrated promising drug PK/PD bioavailability and low toxicity profiles, and can significantly inhibit MM tumor growth (>75%) compared with the control group in in vivo human MM xenograft murine model; and v) p62-ZZ small-molecules induce dramatic new bone formation selectively in MM-containing bones in an immunocompetent mouse model. Thus, the goal of the NIH Fast Track is to carry out IND-enabling preclinical research and development work to advance the discovered/reported small- molecule drug candidates to the next stage for undertaking scale-up chemistry synthesis and IND-enabling toxicology and efficacy investigations. Bringing drug candidates to the defined milestones will fast-track commercialization opportunities via co-development partnerships with major pharma/biotech companies and also significantly enhance the chances of attracting additional private financial investments, leading ultimately to multiple myeloma disease drug clinical trials.