Platform technology for small molecule inhibitors of regulated cellular necrosis
Small molecule inhibitors of regulated cellular necrosis
Previous research on the TNF signaling pathway, as well as very recent data from the Yuan laboratory strongly implicate that necroptosis contributes to a variety of conditions including:
• Ischemic brain injury
• Multiple sclerosis
Furthermore, in vivo data in mouse models of ischemic brain injury and multiple sclerosis show that Nec-1 specifically blocks necroptosis, and ameliorates disease pathology.
Innovations and Advantages
Platform technology opportunity: Necroptosis was identified by the Yuan lab as a regulated, non-apoptotic, form of cell death. This platform technology is based on a novel target and biological mechanism, as well as proprietary compounds, including:
• Multiple necrostatins (inhibitors of necroptosis) discovered via cell-based screening
• RIP1 kinase identified as the target for nec-1 and 12 additional necrostatins
• Novel biological mechanism unveiled, demonstrating that RIP1 kinase is involved as a key pathological mechanism in a variety of conditions, such as MS, Glaucoma and IBD
• Necrostatin effect in these conditions has been validated in vitro and in vivo
• Small molecule screen to identify modulators of necroptosis
• Screening assays to identify necroptosis genes
• Methods of treatment related to a series of novel targets within the necroptosis pathway
Background on cell death: Cell death has been traditionally classified as apoptosis (regulated) or necrosis (passive). Apoptosis is a highly regulated, genetically encoded, caspase-dependent pathway of cell death which plays an important role in the normal development of multi-cellular eukaryotes and in the maintenance of adult organism homeostasis. Alternatively, necrosis is characterized as passive cell death caused by overwhelming stress.
Necroptosis, a novel, regulated form of cellular necrosis: The Yuan lab defined a novel, regulated form of cell death mediated by death receptors, termed necroptosis. Necroptosis is triggered by the same stimuli that normally activate apoptosis, however, this pathway does not involve key regulators of apoptosis such as caspases and Bcl-2 family members. Furthermore, necroptosis is characterized by the same morphological features as unregulated necrosis.
Unprecedented opportunity to selectively target regulated cellular necrosis: Notably, cell death with necrotic features is prevalent in an array of human pathologies and it has become increasingly clear that cells have alternative means to trigger regulated cell death. However, inhibition of necrosis has not been viewed as a viable therapeutic strategy because necrosis is believed to be an unregulated process. The discovery of necroptosis offers an unprecedented opportunity to selectively target regulated cellular necrosis.
Nec-1, a selective and potent inhibitor of necroptosis: The lab developed a small molecule screening assay to identify specific inhibitors of necroptosis, specifically compounds that inhibit cell death induced by TNFα, and that are independent of caspace activation. Screening of ~500,000 compounds led to the identification of more than 20 structurally unrelated, highly potent inhibitors. One of these compounds, Nec-1, was shown to be a selective and potent inhibitor of necroptosis, with no effect on apoptotic cell death. Extensive medicinal chemistry studies generated an optimized inhibitor with an EC50 = 50 nM.
RIP1 kinase as cellular target of necrostatins: The lab showed that necroptosis is a RIP1-dependent pathway for necrotic cell death. Unlike apoptosis, which requires the RIP1 protein (but not the kinase), the Yuan lab showed that the kinase domain of RIP1 alone is sufficient to directly induce necroptosis, and that Nec-1 specifically inhibits RIP1 kinase activity in vitro. Necrostatins may therefore be developed as first-in-class inhibitors of RIP1 kinase.
Necrostatins as next generation TNFα inhibitors: Recent data from Dr. Yuan’s lab demonstrates a novel role for necrostatins, and suggest that necrostatins may be developed as next-generation TNFα inhibitors.
Screening assays to identify necroptosis genes: The Yuan lab developed a genome-wide siRNA screen and identified 666 necroptosis genes. Microarray data revealed increased expression of these genes in the CNS and immune system, and specifically in macrophages, NK cells, dendritic cells, B and T lymphocytes. Secondary assays identified a subset of 25 core genes that are required for necroptosis induced by TNFα.
Intellectual Property Status: Patent(s) pending
An extensive IP portfolio consisting of chemical compositions, methods of treatment, methods of screening based on the discoveries made by the Yuan lab and protecting future products is available for licensing.
Hsu, Emily P.
For further information, please contact:
Michal Preminger, Director of Business Development
Reference Harvard Case #3048