The 999th Meeting of the Northeastern Section of the American Chemical Society
“CoREST Complex-selective HDAC inhibitors promote pro-synaptic effects and represent the potential for promising new therapies to treat synaptopathies”
By Nathan Fuller, Alkermes
Organized by the Medicinal Chemistry Section
of the Northeastern Section, American Chemical Society (NESACS)
Thursday – December 10th, 2020
Director of Chemistry, Alkermes
Bio: Nathan received his Ph.D. from the University of North Carolina at Chapel Hill under the guidance of James Morken working on reductive aldol chemistry and its application to total synthesis of natural products. He then went on to conduct post-doctoral research in the lab of Stephen F. Martin at the University of Texas at Austin on the synthesis of alkaloid natural products. He began his career as a medicinal chemist at Wyeth Research in Cambridge, MA working in the inflammation group, and then joined Satori Pharmaceuticals in Cambridge, MA where he worked on a program targeting gamma-secretase modulators for the treatment of Alzheimer’s disease. In 2013, Nathan began a role at AstraZeneca in Waltham, MA in the Chemistry Innovation Centre, working in the Fragment-Based Lead Generation group. In this role, he worked on a wide range of target classes and therapeutic areas across the AstraZeneca portfolio. In late 2015, Nathan joined the team at Rodin Therapeutics to lead their chemistry efforts to apply HDAC inhibitors to the treatment of synaptic pathology in neurologic disorders. In November of 2019, Rodin Therapeutics was acquired by Alkermes, and Nathan has joined the team at Alkermes to continue to advance the science around novel complex-selective HDAC inhibitors.
Abstract: Synaptic dysfunction is a pathological feature in many neurodegenerative disorders, including Alzheimer’s disease, and synaptic loss correlates closely with cognitive decline. Histone deacetylase enzymes (HDACs) are involved in chromatin remodeling and gene expression and have been shown to regulate synaptogenesis and synaptic plasticity, thus providing an attractive drug discovery target for promoting synaptic growth and function. HDAC1 and HDAC2 associate with multiple co-repressor complexes including CoREST, which regulates the expression of many neuronal genes. We have identified a series of novel HDAC inhibitor compounds that selectively inhibit the HDAC-CoREST complex, resulting in increases in dendritic spine density and synaptic proteins, and improved long term potentiation in a mouse model at doses which provide a substantial safety margin that would enable chronic treatment. This approach represents the potential for promising new therapeutic strategies in targeting synaptic pathology involved in multiple neurologic disorders.