A Role for KSHV in the Pathogenesis of Malignancies

Division Of Clinical Sciences - Nci

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Abstract

We have pursued analysis of the specific mechanisms by which SJ6986 and CC90009 inhibit endothelial cell proliferation. After testing the anti-endothelia and anti-angiogenic activities of most of the IMIDs previously used clinically or developed but not used as human therapeutics, we have identified SJ6986 and CC90009 as unique in their effective inhibition of endothelial cell proliferation in vitro and anti-angiogenic activity in vivo. We have conformed that these two compounds induce GSPT1 degradation in human endothelial cells to a similar degree as noted in leukemia and lymphoma cells. However, we we have demonstrated that GSPT1 degradation is not responsible for the inhibition of endothelial cells. We have discovered the transcription factor FOXO1 as a new target for degradation by SJ6986 and CC90009. Further, we have demonstrated that the degradation of FOXO1 is responsible for the inhibition of endothelial cell proliferation by SJ6986 and CC90009. It was previously known that FOXO1 is a transcription factors that plays essential roles in endothial and vascular development. It was also known that FOXO1 is required for function of postnatal endothelial cells. However, it was not previously known than IMIDs can induce FOXO1 degradation and no other protein degradar for FOXO1 has been previously developed. Possession of a drug that can simultaneously degrade GSPT1, which has a well-documented anti-tumor activity, and FOXO1, which impairs the endothelial cells and the vasculature is an advance. The biochemistry sustaining the FOXO1-degrading function of SJ6986 and CC90009 is particularly notable. SJ6986 and CC90009 require binding to CRBN-DDB1 to induce FOXO1 degradation. However, preliminary structural studies indicate that FOXO1 does not bind directly to CRBN, as GSPT1 does, but elsewhere in the complex that includes several protein components. Current studies are now focused on defining the FOXO1 binding partners and the effects of this binding to the overall structure. A manuscript describing these findings has been drafted along with its figures, and we hope to submit it for consideration of publication in the next few weeks.