Antagonizing the SET Oncoprotein

DESCRIPTION provided by applicant We discovered that the SET oncoprotein is overexpressed in of biopsy samples from patients with hematological cancers and about of biopsy samples from patients with solid tumors Vitek et al US Patent and Also known as I PP A one of SETandapos s normal functions is to inhibit Protein Phosphatase A PP A Hahn showed that cancerous transformation of human cells required inhibition of PP A Of the known PP A inhibitors only SET has been reported to be druggable We discovered that apolipoprotein E apoE and the apoE mimetic peptide spanning residues specifically bound SET Fig Upon binding of apoE to SET cellular PP A activity levels increased supporting that apoE is a SET antagonist Fig andamp But most importantly the SET antagonist known as OP is also an apoE peptide mimetic that kills human cancer cells in vitro and in xenografted orthotopic tumors from both hematological and solid tumors Together these data strongly support that antagonism of SET is a useful target for anti cancer targeted drug development Since OP is an injectable peptide we propose a step screening cascade Figure to find orally active small molecule antagonists of SET that will permit re activation f PP A and the death of cancer cells In this Phase grant we will initiate Steps andamp of screening cascade We seek support in this proposal to use our High Throughput Screen HTS to find small molecule SET binders Hits from this HTS assay will then be subjected to an orthogonal assay where the toxicity of each hit to a cancer cell line and to a normal cell line wil be evaluated Additional orthogonal assays to further confirm the usefulness of hit compounds will be pursued in future applications Similar screens to find small molecules that disrupt protein protein interactions PPIs have for example yielded several small molecules including Nutlin a which disrupts p MDM binding The MDM disruptor AMG is about to start and Nutlin RG is currently in clinical trials where it has shown anti cancer activity in patients PUBLIC HEALTH RELEVANCE The nd leading cause of death in the US is from cancer Our research has uncovered a useful cancer target known as the andquot SET oncoprotein andquot SET normally inhibits the tumor suppressor known as Protein Phosphatase A PP A We have identified a peptide that binds to SET thereby inhibiting SETandapos s activity and allowing the PP A tumor suppressor to be re activated and kill the cancer cells In this proposal we are requesting support to begin the screening process to identify orally active small molecules that act like our peptide in binding to SET and allowing the PP A tumor suppressor to be re activated and kill the cancer cells These molecules are now called Phosphatse Activating Drugs or PADs and represent a new class of anti cancer drugs that complement and synergize with existing targeted kinase inhibitor drugs such as Gleevec