Alzheimer’s disease | Protekt Theraputics | Ness Ziona
ProteKt Therapeutics develops potent and selective inhibitors of the kinase PKR for the treatment of neurodegenerative and neuroinflammatory diseases
ProteKt Therapeutics has discovered and developed a series of novel and selective molecules by applying unique computational methods and validating the inhibitors in clinically relevant assays
ProteKt is a graduate of the FutuRx Biotechnology incubator - a joint venture of J&J, Takeda and Orbimed partners
Alzheimer’s Disease (AD) is an irreversible, progressive brain disorder that slowly destroys memory and thinking skills, and, eventually, the ability to carry out the simplest tasks. In most people with AD, symptoms first appear in their mid-60s. Estimates vary, but experts suggest that more than 5.5 million Americans, most of them age 65 or older, may have dementia caused by AD.
Alzheimer's Disease is the most common cause of dementia among older adults. Dementia is the loss of cognitive functioning—thinking, remembering, and reasoning—and behavioral abilities to such an extent that it interferes with a person’s daily life and activities.
Alzheimer's Disease is complex, and it is hard to treat. Current treating approaches focus on helping people maintain mental function, manage behavioral symptoms, and slow down certain problems, such as memory loss. None of the medications available today for AD dementia slow or stop the damage and destruction of neurons that cause AD symptoms. To date, six drugs were approved in the US for the treatment of AD, most of these drugs temporarily improve symptoms by increasing the amount of chemicals called neurotransmitters in the brain. The effectiveness of these drugs varies from person to person and is limited in duration.
No new Alzheimer's Disease drug has been approved since 2003 and in recent years, most of the efforts were to develop a drug that target amyloid beta. Due to many failures of this approach, there is a real need to explore novel therapeutic mechanisms that may lead not only to cognitive improvement but also will slow down or even inhibit the progress of the disease.
Double-stranded RNA-activated protein kinase, or PKR, is a pro-apoptotic kinase that controls the initial step of protein translation through the phosphorylation of the eukaryotic initiation factor 2 alpha (eIF2α). This control of protein translation machinery results in inhibition of protein synthesis in response to cellular stress, a process known the Integrated Stress Response (ISR). The reduction in protein translation is believed to result in memory consolidation impairment, which may lead to cognitive disfunction.
PKR is involved in several cellular pathways including innate immunity and defense against viruses. PKR can sequentially induced cell survival and death pathways and also modulates the synthesis of pro-inflammatory factors via the activation of the NF-kB pathway. PKR is also involved in the control of the inflammasome and HMGB1 release. This kinase is highly expressed in degenerative neurons in AD brains and can be activated in primary neuronal cultures by Amyloid β. In addition, the levels of activated PKR are highly increased in the cerebrospinal fluid (CSF) of patients suffering from Alzheimer's Disease or Mild Cognitive Impairment and can correlate with the cognitive decline in AD patients. PKR is involved in neuroinflammation, apoptosis, autophagy and Aβ-induced toxicity, which are all prominent features of AD, and therefore is a good target for drug development for AD.
PKR inhibition is a novel mechanism for modulating multiple key processes in AD and other neurodegenerative diseases. This multimodal approach may overcome many of challenges that hindered the ability of other drug candidates to successfully change the course of neurodegenerative diseases. This approach is supported by a strong and growing body of preclinical and human evidences.
ProteKt uses state of the art computational and biochemical approaches to identify novel potent and selective proprietary small molecules inhibitors of PKR. We established set of assays to characterize and test the potency of these new families of inhibitors. Using the techniques we established, we identified several potent hit families of PKR inhibitors, demonstrated their in vitro activity in models relevant for AD, and aims to further develop them into a promising drug.
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