Therapeutic approaches to preventing cell death in Huntington disease

Abstract

Neurodegenerative diseases affect the lives of millions of patients and their families. Due to the complexity of these diseases and our limited understanding of their pathogenesis, the design of therapeutic agents that can effectively treat these diseases has been challenging. Huntington disease (HD) is one of several neurological disorders with few therapeutic options. HD, like numerous other neurodegenerative diseases, involves extensive neuronal cell loss. One potential strategy to combat HD and other neurodegenerative disorders is to intervene in the execution of neuronal cell death. Inhibiting neuronal cell death pathways may slow the development of neurodegeneration. However, discovering small molecule inhibitors of neuronal cell death remains a significant challenge. Here, we review candidate therapeutic targets controlling cell death mechanisms that have been the focus of research in HD, as well as an emerging strategy that has been applied to developing small molecule inhibitors-fragment-based drug discovery (FBDD). FBDD has been successfully used in both industry and academia to identify selective and potent small molecule inhibitors, with a focus on challenging proteins that are not amenable to traditional high-throughput screening approaches. FBDD has been used to generate potent leads, pre-clinical candidates, and has led to the development of an FDA approved drug. This approach can be valuable for identifying modulators of cell-death-regulating proteins; such compounds may prove to be the key to halting the progression of HD and other neurodegenerative disorders.

Figure 1

Strategies for optimizing fragments into “drug-size” compounds. Fragment growing/evolution strategy (a) is most similar to the traditional hit-to-lead optimization process. The active fragment (red) is chemically modified until a new chemical moiety (green) improves the binding affinity for the target by acquiring additional contacts with the target. The process can be further iterated to incorporate more favorable functional groups and interactions (purple). Structural binding information is not necessary for this method, but it does minimize the time for chemical optimization. Computation modeling can also facilitate in this process. A fragment linking strategy (b) requires knowing structurally where the fragments interact with the target protein. Active fragments in the neighboring binding pocket (red and blue) can be linked together to optimize potency for the protein. Care must be taken however, in designing the linker not to alter the original binding pose of the active fragments. The fragment tethering approach (c) makes use of a modified fragment library, designed to contain a single disulfide bond on each fragment, and an endogenous or engineered cysteine near the binding pocket of the protein. Under mild reducing conditions the fragment that has an affinity for the protein will be able to form a stable disulfide bond with the target (red). This active fragment can then be modified to include a thiol group that will be able to react with another disulfide fragment (purple). Lastly, the disulfide linker between the two active fragments is replaced by another more rigid linker. Figure adapted from (Erlanson, 2011).