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Lay abstract (no permission to release technical abstract): Multiple Myeloma (MM) is a malignancy of plasma cells that accounts for 2% of all cancer deaths. It is currently incurable. Kinase inhibitors are the fastest growing class of anti-cancer drug, both because of their efficacy and relative feasibility of design. However, a lack of effective kinase targets in MM has delayed successful use of kinase inhibitors for this cancer. We have previously tested all kinases in MM tumor cells to identify Achilles heel vulnerabilities. Fifteen kinases were consistently required for MM cell survival, including many known for roles in cancer. However most kinase vulnerabilities were not tumor-specific as inhibiting these kinases proved equally lethal to many cell types. Importantly, one kinase, GRK6, is selectively vulnerable only in MM cells; inhibiting GRK6 is tolerated in other cells. GRK6 is almost always expressed in MM, but is absent or only weakly expressed in most human tissues. The ability to 'drug' GRK6 without causing excessive toxicity is demonstrated by GRK6-deficient mice, which are healthy. In humans, mutations that cause loss of GRK6 interaction with CXCR4 cause WHIM syndrome, characterized by plasma cell deficiency and hypogammaglobulinemia, confirming that GRK6 is required for plasma cells in vivo. We propose developing GRK6 kinase inhibitors as therapeutics. GRK6 drugs have not previously been described. We have purified GRK6 and developed kinase- and cell-based assays to screen for selective inhibitors. We will use high-throughput screening of large compound libraries, focused biological assays, X-ray analysis of GRK6-drug interaction and directed synthesis of novel compounds to develop drugs that selectively inhibit GRK6, but not other kinases. Their medicinal properties will be examined and the best drugs will be advanced to studies using MM cell lines, tumor samples and animal models of MM. We seek to translate our discovery of an Achilles' heel within plasma cells into a drug to treat MM and related diseases.

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