We previously reported the anti-tumor and anti-angiogenic activity of a new class of sangivamycin-like molecules (SLMs). In this study we aimed to further the preclinical development of these compounds by identifying tumor types with the highest sensitivity to their cytotoxic effects. Of 35 tumor cell lines from 8 different tissues of origin that we screened, we found that multiple myeloma (MM) cells were approximately 3–10 times more sensitive to SLMs than other tumor types. SLM3 as well as SLM5, SLM6, and SLM7 reduced viability and induced apoptosis of MM cells at sub-micromolar concentrations in vitro. By contrast, SLMs induced negligible amounts of apoptosis in other tumor and normal cell lines. SLM6 exhibited the most potent activity in vivo where it significantly inhibited the growth of xenografted MM tumors. We found that SLM6 inhibited cyclin dependent kinase 9 (CDK9) resulting in hypophosphorylation of RNA polymerase II (Ser2) and transcriptional repression of oncogenes that are known to drive MM progression and resistance to therapy (c-Maf, cyclin D1, c-Myc, L-Myc, and Mcl-1). Furthermore, we found that SLM6 increased the cytotoxic activity of therapies that are currently approved for MM treatment (bortezomib, lenalidomide, dexamethasone, and doxorubicin). These findings suggest that CDK9 inhibition is a particularly effective targeted strategy for MM, and SLM6 is a promising CDK9-targeted agent, both as a single agent and in combination with currently approved therapies.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C77.