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Selective Disruption of Histone Deacetylase Complexes by Protein Interaction Inhibitors to Treat Cancer and Neurological Disorders
Dana-Farber
Small molecule
Neurology, Oncology
Hit To Lead or Lead Optimization
Overview
Enzymes do not always function in isolation, but rather they function in conjunction with many other proteins to form complexes. A known example is histone deacetylase (HDAC)-based transcriptional machinery which regulates gene expression by removing acetyl groups from histone tails. These enzymes have been demonstrated to play key roles in many diseases such as cancer, Alzheimer’s disease, Parkinson’s disease, schizophrenia, etc. In humans, there are 11 zinc-dependent HDAC enzymes which contain a highly conserved catalytic pocket across all forms. There are FDA approved HDAC inhibitors that target the enzymatic pocket of HDACs to prevent deacetylation which in turn alters transcription of the downstream gene. Nonetheless, a significant challenge remains to target a specific HDAC form over other HDAC forms due to the promiscuity of the enzymatic pockets. Even if only one could be selected, there would be no differentiation between the different complexes formed in the different pathways in which HDACs are involved. There is a need to develop HDAC inhibitors with more specificity and Dana‑Farber inventors found that targeting HDAC complex interaction could potentially achieve such goals.
Researchers at Dana-Farber Cancer Institute have identified a class of novel inhibitors that bind to the paired amphipathic helix (PAH) domain of SIN3, a scaffold protein of HDAC complexes. The scaffold protein SIN3 interacts with other proteins via its paired amphipathic helix (PAH) domain, and the identified inhibitors break the interaction with transcription factors or DNA binding proteins. The inhibitors have similar biological effects as other already established HDAC inhibitors, with the key difference that fewer genes are perturbed in mammalian cells as well as in psychosis mouse models.
Benefits
• This new class of HDAC inhibitors disrupts the transcriptome of cancer cells more specifically than enzymatic inhibitors like trichostatin A
• Compared to trichostatin A (an establish HDAC inhibitor) there was a 20-fold drop in the number of genes perturbed in neuroblastoma cells
• There was also a 50-fold drop in the number of genes perturbed in HDAC2 knockout mice
Marc Vidal, Julien Olivet, Soon Gang Choi
PCT-US2022-034043 (2022.06.17)
Patent Family: PCT
"Expanding the HDAC druggable landscape beyond enzymatic activity". Olivet, J. et al. bioRxiv 2023 January 14.(Cold Spring Harbor Laboratory).
