ABSTRACT Rgenta has developed a robust, innovative, target and lead discovery platform that has identified small molecules that can lower the levels of HTT through a novel mechanism-of-action in RNA-targeting. In this Phase I SBIR project, we aim to develop first-in-class drug candidate compounds for HTT lowering as a new therapeutic approach for treating HD. Our Phase I SBIR proposal has three aims: Aim 1. We will perform chemical hit expansion and medicinal chemistry to improve the potency and refine Structure-Activity Relationships (SARs) of our three novel pharmacophores. Aim 2. We will characterize pharmacological effect of lead molecules in HD patient derived iPSC neurons on HTT lowering, preventing HTT aggregate formation induced by proteasome inhibitors, and selectivity profiles Aim 3. We will test up to five compounds from each chemical series in well- established in vitro absorption, distribution, metabolism, excretion (ADME) assays including cell permeability, and in vitro metabolic stability. We will then determine mouse in vivo pharmacokinetics (PK) on the best molecules. Aim 4. We will determine the in vivo HTT lowering efficacy of our best compounds in HD mouse models.