Discovering a Small Molecule that Targets the KSHV Processivity Factor for Treating Oral and Systemic Kaposi Sarcoma

Kaposi SarcomaKSis the most common cancer in themillion worldwide AIDS populationKS tumors are caused by Kaposi Sarcoma Associated Herpes VirusKSHVEven though HAART therapy has resulted in a dramatic decline in KS in the USthis malignancy remains the most predominant tumor of AIDSParadoxicallyKS tumors arise in some AIDS patients following HAART treatmentdue to Immune Reconstitution Inflammatory SyndromeKS is a systemic cancer that can form on the skinoral cavity and internal organsThese tumors grow on the hard and soft palategingivatongueuvulapharynxtrachea and tonsilsKS oral tumors are painfulextremely angiogenicand can ulcerate and interfere with mastication of foodcause tooth lossimpede speechand hinder breathingOral KS thus not only compromises the quality of life but threatens survivalOf significancethere is no drug for treating KSmaking this viral cancer an unmet medical needOur long term goal is to develop a drug for treating acute Oral KS by injection into tumors and sustained systemic treatment by oral capsule deliveryNotablya small number of KSHV lytically infected cells within KS tumors are critical for maintaining malignancyWe have discovered a KSHV proteinProcessivity FactorPFwhich is essential for KSHV DNA synthesis and lytic infectionmaking PFan ideal drug target to treat KSWe showed PFassociates with KSHV DNA polymerasePolenabling it to incorporate nucleotides continuously without dissociating from the template and that PFis specific for PolWe also revealed by crystallography that PFforms head head homodimers and identified domains required for dimerization and stabilization of Polon the DNAOur FIRST AIM is to identify Leads by two approachesApproachis to extend our successful pilot screen of acompound Chemical Diversity Library using our Rapid Plate Assay designed to specifically identify functional inhibitors of PFOur pilot screen ofcompounds has already produced four HIT small molecules that specifically block processive DNA synthesis and KSHV infection in cellsApproachis to test peptidomimetics and small molecules synthesized by mutation structure guided design to prevent formation of PFhomodimersThis approach is based on our crystal structure of PFand recent site directed mutagenesis which revealed that each of five individual and consecutive amino acidsSTVHKthat compose the Beta Sheet needed for homodimerizationis necessary for processive DNA synthesisOur SECOND AIM is to use a proven iterative medicinal chemistry SAR approach to test for potency in blocking PFprocessive DNA synthesisinhibition of KSHV infection in cellstoxicity and validation of binding by IsoThermal CalorimetryITCOur THIRD AIM is to evaluate the top Leads from AIMfor In Vitro ADME and Off Target Activity by tests that includeAqueous SolubilityMetabolic StabilityPlasma Protein BindingPPBCYPInhibition and hERG Patch Clamp NARRATIVE Our ultimate goal is to develop the first approved drug for treating Oral and Systemic Kaposi SarcomaKSwhich remains the most common tumor that occurs in individuals with AIDSOral KS compromises the quality of life and threatens survival by interfering with eating andin some casesbreathingThe future end point is to produce an effective and safe drug for both acute oral and systemic treatment of KS