CC102528: A Novel Histone Deacetylase Inhibitor in the Hydroxamate Family Demonstrates Potent Anti-Myeloma Activity.

Abstract 4927

Despite advances in the treatment of multiple myeloma (MM), the disease remains incurable. Thus, there is a need for the development of new drugs to improve the outcome for patients with this common B-cell malignancy. Histone acetylation, which is controlled by the balanced activities between histone acetyltransferase (HAT) and histone deacetylase (HDAC), is a major epigenetic modification that may contribute to tumorigenesis. Through inhibition of HDAC activity, HDAC inhibitors (HDACis) increase acetylation level of histones as well as other tumor suppressor gene products; and, therefore, are potential anti-cancer agents. Based on the structures, currently available HDAC inhibitors can be divided into four groups, including hydroxamates, cyclic peptides, aliphatic acids, and benzamides. We have screened a library of combined compounds and identified two potential novel HDACis (CC102528 and CC102598) that demonstrate potent anti-MM effects in vitro. Both compounds are hydroxamate derivatives with IC₅₀ below 5 μM in the MM cell line RPMI8226 as determined with the MTS assay. These compounds induce apoptotic cell death and inhibit HDAC activity in MM cells as determined with Annexin V staining followed by flow cytometric analysis and acetylation status of histones, respectively. Interestingly, only CC102528, but not CC102598, caused death of nearly all MM cells when used at 10 μM or 20 μM. These results suggest that CC102528 blocks HDACs more efficiently than CC102598, or CC102528 targets additional intracellular molecules that are also responsible for its greater anti-MM activity. These results suggest that CC102528 could be a potential novel agent for the treatment of MM. We are currently evaluating the anti-MM effects of this compound in combination with other currently available agents for the treatment of MM including bortezomib, melphalan, dexamethasone, and doxorubicin. We are also determining the effects of this drug alone and in these combinations on normal peripheral blood and bone marrow mononuclear cells. In addition, modifications of CC102528 are being made, and we will determine if these newer analogs improve upon the anti-MM effects of the parent compound. Updated data from these additional studies will be reported at the meeting.