Next-Generation CNS-Penetrant HDAC6 Inhibitors: Proof-of-Principle in Parkinson's Disease

Summary: Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by loss of do- paminergic neurons (DANs) leading to severe motor and non-motor symptoms. Despite the availability of dopa- mine replacement therapies, there remains a critical need for disease-modifying treatments that can address the underlying pathologies of PD. Recent research suggests overactivity of histone deacetylase 6 (HDAC6) as a contributing factor in the pathogenesis of PD. HDAC6 deacetylates key cytoplasmic proteins like alpha-tubulin and tau, and both are hypoacetylated in PD, supporting HDAC6 hyperactivity. HDAC6 inhibition has shown promise in preclinical models, demonstrating protective effects against alpha-synuclein toxicity, oxidative stress, and neuroinflammation, thereby enhancing DAN survival. Yet, the development of HDAC6 inhibitor therapeutics has been limited by challenges in achieving potency, selectivity, brain penetrance, and demonstrable target engagement in the human brain. Eikonizo is developing a new class of potent, selective, and brain-penetrant HDAC6 inhibitors, overcoming previous limitations and introducing promising candidates for disease-modifying PD therapy. The proposed Phase I SBIR project aims to evaluate the efficacy of Eikonizo development candi- date EKZ-102 in reducing pathological markers of PD and improving DAN survival in both in vitro and in vivo models through the following Specific Aims: 1) establish proof-of-principle of EKZ-102 for treatment of PD in vitro by assessing impact on alpha-synuclein pathology, oxidative stress, and DAN survival in rodent and human iPSC-derived DAN cultures; and 2) define the therapeutic potential of EKZ-102 in an animal model of PD featur- ing striatal alpha-synuclein preformed fibril lesion to mimic key aspects of PD pathology. The successful com- pletion of the proposed project will validate the disease-modifying potential of EKZ-102 inhibitors in preclinical models, setting the stage for an FDA pre-IND meeting and completion of IND-enabling studies.