Enhancing cytarabine response through SAMHD1 inhibition

The overall goal of this collaborative proposal is to investigate whether inhibition of SAMHD1 can be used to potentiate effectiveness of cytarabine in treatment of AML. ALL and other childhood and adult cancers.UTSA and Dr. McHardy???s lab will provide all of the synthesis and medicinal chemistry support for this collaborative proposal.In Aim 1 we will follow up on any identified hits from the high-throughput screening efforts carried out at UT Health SA in the CIDD core facility.This will include the re-synthesis of the hit compounds to confirm structure. purity and SAMHD1 activity. as well as perform analog synthesis to develop SAR studies to improve SAMHD1 activity and physicochemical properties.In year 2. we plan to design and synthesize novel synthetic oligonucleotide analogs containing phosphorothioate bonds. based on new structural and binding insights developed in Dr. Ivanov???s lab.We will also perform SAR studies to optimize the potency and properties of these oligionucleotides.All compounds prepared in the McHardy lab at UTSA will be fully characterized by 1H and 13C NMR. and HPLC/MS. targeting a chemical purity of >96% and will be registered in the CIDD compound file. and assigned a CIDD identification number.Small retains (2-5 mg) will be held at the CIDD medicinal chemistry core facility and 15-20 mg of each compound will be sent to Dr. Ivanov???s lab for in vitro assessment.