TRPM4

FundaMental Pharma GmbH announces publication of a groundbreaking Proof-of-Concept Study in Cell Reports Medicine using a TwinF Interface Inhibitor for the Treatment of Amyotrophic Lateral Sclerosis 7 February 2024 – FundaMental Pharma GmbH (‘FundaMental’ or ’the Company’), a neuroscience company developing first-in-class small molecule inhibitors for treatment of a range of neurodegenerative diseases, today announces the publication of a groundbreaking study by Neurobiologists in Heidelberg using FundaMental Pharma’s small molecule TwinF interface inhibitor, FP802. The study provides seminal preclinical proof-of-concept data for the treatment of amyotrophic lateral sclerosis (ALS). The research team led by Heidelberg University Professor Hilmar Bading, who is co-founder of FundaMental Pharma, showed that FP802 treatment resulted in reduced neurological scores and mortality in a gold standard mouse model of ALS. Most importantly, the validated ALS clinical biomarker neurofilament light chain (Nf-L) was reduced in line with the positive treatment effects. The team went further to demonstrate that FP802 also protected human ALS patient-derived brain organoids from glutamate neurotoxicity, a key driver of ALS pathogenesis, highlighting the likely translatability of the preclinical findings to patients. FundaMental Pharma is engaged in pioneering research around a breakthrough molecular mechanism that allows it to safely counteract glutamate neurotoxicity (also known as excitotoxicity) by specifically targeting the interface between NMDA receptors and TRPM4 with small molecule TwinF interface inhibitors (Yan et al., Science 2020). TwinF interface inhibitors constitute an entirely new class of drugs that safely ameliorate glutamate neurotoxicity, a common cause of neurodegeneration. Thomas Schulze, Chief Executive Officer, Co-Founder of FundaMental Pharma, commented: “As we are currently in the process of developing orally bioavailable TwinF interface inhibitors, this latest publication by our academic co-founder provides tremendous validation of our work and guides us towards ALS as prime indication for our new medicines.” Professor Hilmar Bading, Co-Founder of FundaMental Pharma, added: “The success of FP802 in protecting brain organoids derived from human ALS patients underscores the translatability of our preclinical findings, offering a glimpse into the potential impact of TwinF interface inhibitors on patients." FundaMental Pharma (“FundaMental”) is a neuroscience company, spun out of Heidelberg University, developing first-in-class small molecule inhibitors for treatment of a range of neurodegenerative diseases. FundaMental scientists are developing an entirely new class of drugs that safely counteract glutamate neurotoxicity, a common cause of neurodegeneration. While FundaMental’s current focus is on Amyotrophic Lateral Sclerosis (ALS) and Huntington’s Disease, the applicability of these molecules could extend to a range of neurogenerative disorders such as dementia and aging-related memory loss. For more information, please visit: www.fundamentalpharma.com The content above comes from the network. if any infringement, please contact us to modify.

A new pharmacological inhibitor can intervene in a central cell death mechanism that is responsible for the death of motor neurons and hence important for the progression of the motor neuron disease amyotrophic lateral sclerosis (ALS). Neurobiologists examined a neuroprotective molecule that belongs to a novel drug class. It is able to inhibit the interactions of certain proteins and has been successfully tested in a mouse model of ALS and in brain organoids of ALS patients. A new pharmacological inhibitor can intervene in a central cell death mechanism that is responsible for the death of motor neurons and hence important for the progression of the motor neuron disease amyotrophic lateral sclerosis (ALS). A research team led by Prof. Dr Hilmar Bading, neurobiologist at Heidelberg University, examined a neuroprotective molecule that belongs to a novel drug class. It is able to inhibit the interactions of certain proteins and has been successfully tested in a mouse model of ALS and in brain organoids of ALS patients. "On the long road to an effective treatment for ALS patients, these findings from basic research may represent a significant step forward," says Prof. Bading. ALS is a degenerative disease of the nervous system particularly affecting and harmful to motor neurons. As the disease progresses, the nerve cells controlling voluntary muscle movement die. That leads to a progressive wasting of the muscles responsible for moving and speaking, but also for eating and breathing. To date, says Prof. Bading, there is no effective drug treatment for ALS patients, who in most cases die within two to five years after the diagnosis. The FP802 molecule the Heidelberg scientists used in the study belongs to a new pharmacological class of drugs. These are "TwinF interface inhibitors," which were discovered by Prof. Bading and his team at the Interdisciplinary Center for Neurosciences (IZN) of Heidelberg University. These inhibitors disrupt the physical interactions of two ion channel proteins, with the names NMDA receptor and TRPM4, which, due to a so-called protein pocket named "TwinF" by the Heidelberg scientists, form a protein-protein complex. NMDA receptors are found on the cell surface of nerve cells and are present both in the synapses, the contact points between the nerve cells, and outside these contact points. They are activated by a biochemical messenger substance, the neurotransmitter glutamate. The stimulation of synaptic NMDA receptors in the brain contributes to learning and memory processes, as well as to protecting nerve cells. Outside the synapses, however, the activation of these receptors leads to a damaging of nerve cells and to their death. The team around Hilmar Bading investigated the reasons for this in a prior study. They found out that TRPM4 confers toxic properties to the extrasynaptic NMDA receptors in the brain. Together these two proteins form a "death complex," which also plays a role in ALS. The neuroprotective molecule FP802 binds to the TwinF protein pocket of TRPM4, blocks the contact areas of the interacting proteins, and thereby disrupts the fatal complex of NMDA receptors and TRPM4. The Heidelberg scientists have studied this new drug principle using an ALS mouse model as well as brain organoids of ALS patients. "With this completely new therapeutic concept in combating neurodegenerative diseases we were able to achieve remarkable outcomes," says Prof. Bading. The scientist explains that it was possible to prevent cell death and hence the loss of spinal motor neurons of mice by giving them the neuroprotectant. This treatment improved their motor abilities, mitigated the progression of the disease and extended the lifespan of the animals. "The discovery of this new pharmacological class of drugs opens up a promising path for fighting ALS. A long-term goal is to develop TwinF interface inhibitors for use in patients," says Hilmar Bading. In close cooperation with the startup FundaMental Pharma, a Biotech offshoot of the IZN Department of Neurobiology, the molecule FP802 is to be optimised for use in humans in the coming years and tested for efficacy in clinical trials. Dr Jing Yan, who was involved in the latest study, recently joined FundaMental Pharma in order to accelerate the further development of FP802. The research was funded by the German Research Foundation, the European Research Council and the Alexander von Humboldt Foundation.

Scientists have identified a protein that plays a pivotal role in the action of several emerging cancer therapies. The researchers say the discovery will likely aid efforts to fine-tune the use of immunotherapies against several challenging cancers. Scientists have identified a protein that plays a pivotal role in the action of several emerging cancer therapies. The researchers say the discovery will likely aid efforts to fine-tune the use of immunotherapies against several challenging cancers. They report their findings in the journal Cancer Research. "Most anticancer drugs cause cancer cells to shrivel up and die in a controlled process known as apoptosis. But apoptosis does not usually strongly activate immune cells," said David Shapiro, a professor of biochemistry at the University of Illinois Urbana-Champaign who led the research with former graduate student Santanu Ghosh. "However, a few emerging cancer therapies cause cancer cells to swell up and burst. The protein we identified, a sodium-ion channel known as TRPM4, is critical for cancer therapies that promote this type of cell death, called necrosis." Unlike apoptosis, necrosis strongly signals the immune system to target and cleanup the remains of the dying cells, Shapiro said. "This suggests that treatments that promote necrosis may improve immunotherapies against solid tumors," he said. TRPM4 is the first protein mediator of anticancer therapy-induced necrosis to be described, Shapiro said. In previous work, Shapiro, U. of I. chemistry professor and study co-author Paul Hergenrother and their colleagues developed two drugs -- a compound called BHPI and later, a more effective agent known as ErSO -- that spur necrosis in solid tumors, dramatically shrinking and often eradicating primary and metastatic tumors in mice. These drugs work by binding to estrogen receptors on cancer cells and pushing a normally protective cellular stress-response pathway into overdrive. This pathway, the "anticipatory unfolded protein response, or a-UPR," ultimately causes the cell to swell, leak and die. "Even though we identified the initial steps in the a-UPR pathway that kills cancer cells, the specific proteins that mediate cell swelling, rupture and rapid necrotic cell death remained unknown," Shapiro said. To identify the relevant proteins, Shapiro and his colleagues screened breast cancer cells by knocking out each of the roughly 20,000 individual genes in the cancer cells and then treating the altered cells with BHPI or ErSO. Cells that resisted treatments with these agents revealed which genes were essential to the drugs' effectiveness. The researchers were surprised to find that TRPM4 emerged as a key driver of the process of necrosis in cancer cells treated with ErSO and BHPI. The team also found that TRPM4 was important for the activity of several other necrosis-inducing cancer therapies. "This will enable physicians to identify patients most likely to benefit from necrosis-inducing therapies because their cancers have high TRPM4 levels," Shapiro said. Further study revealed that an ErSO-induced increase in intracellular calcium causes the TRPM4 channel to open, allowing sodium ions and water to flow into the cell. The influx causes the cell to swell, rupture and leak, activating immune cells and causing them to rush to the site of the dead cells. "Cancer treatment has been transformed by immunotherapy, which takes the brakes off immune cells, enabling them to attack cancer cells," Shapiro said. "But immunotherapy has had limited success against solid tumors such as ER-positive breast cancer and pancreatic cancer." By targeting the TRPM4 pathway in solid tumors, scientists may further enhance the necrosis-inducing anticancer therapies available to fight such tumors, he said. "We found that the cancer drug ErSO acts like the starter on a car that turns over the engine and then is no longer needed once the engine is running," Ghosh said. "It is the swelling caused by TRPM4 that drives the lethal stress that kills the cancer cells. As little as a one-hour exposure to ErSO effectively killed cancer cells days later." The National Institutes of Health, the Cancer Center at Illinois, the Department of Defense Breast Cancer Research Program, the Susan Komen Foundation and the Breast Cancer Research Foundation supported this research. Hergenrother is the deputy director and Shapiro is a researcher in the Cancer Center at Illinois. Hergenrother also is an affiliate of the Carl R. Woese Institute for Genomic Biology and the Carle Illinois College of Medicine at Illinois. Ghosh is now a postdoctoral researcher at the University of Pennsylvania Perelman School of Medicine. Co-authors of the study also include undergraduate student Rachel Yang, graduate students Darjan Duraki, Junyao Zhu, Ji Eun Kim, Musarrat Jabeen, Xinyi Dai, Mara Livezey and Matthew Boudreau; research scientist Chengjian Mao; U. of I. molecular and integrative physiology professor Erik Nelson; and professor Ben Park, of Vanderbilt University College of Medicine.