Khondrion, a clinical-stage biopharmaceutical company discovering and developing therapies targeting mitochondrial disease, today announces the publication of new research in PLOS ONE examining the in vivo active metabolite of sonlicromanol, as a selective inhibitor of microsomal prostaglandin E synthase-1 (mPGES-1)-mediated PGE2 synthesis in prostate cancer stem cells and its potential as a novel treatment approach for prostate cancer and other cancers with high mPGES-1 expression.
Sonlicromanol (KH176) is Khondrion’s wholly-owned investigational lead asset, currently in phase IIb development as a potentially disease-modifying treatment for mitochondrial disease. The Company has previously demonstrated the ability of sonlicromanol’s active metabolite to selectively inhibit mPGES-1, a key enzyme involved in the production of prostaglandin E2. This prostaglandin, known to induce and propagate the inflammation response, was found in significantly increased levels in cells derived from mitochondrial disease patients. Importantly, the aggressiveness of cancers, like prostate cancer, has also been found in independent studies to be associated with elevated expression of mPGES-1.
The new research, authored by Khondrion, details the effects of selective mPGES-1 targeting by sonlicromanol’s active metabolite, and examines its potential to decrease the aggressiveness of prostate cancer by inhibiting mPGES-1 expression.
The research team found that inhibition of mPGES-1 by sonlicromanol’s metabolite was able to considerably reduce spheroid growth in the human prostate cancer cell line DU145, potentially offering a novel approach in treating prostate cancer and other malignancies with high expression of mPGES-1. Sonlicromanol’s active metabolite was found to reduce the constitutively high mPGES-1 levels. The growth of spheroids in a physiological relevant 3D environment for tumour cells was reduced and the prostate cancer stem cell population was selectively decreased. These findings are of particular interest as they further strengthen earlier research indicating the potential of sonlicromanol [human plasma exposure at steady-state: active metabolite = ½ KH176] as a treatment for patients with high mPGES-1 expression and signal its potential as an anti-tumour drug, based on its ability to decrease the size of cancer stem cell-formed spheroids.
Dr. Herma Renkema, Chief Early Development Officer at Khondrion and co-author of the paper, said: “These are significant findings that build on our earlier research into the anti-inflammatory effect of sonlicromanol and its potential as a disease-modifying drug for patients with mitochondrial disease. That research led us to explore the potential of this compound beyond mitochondrial disease, given what we know about its mode of action. Inhibition of mPGES-1 expression is an approach currently being investigated to identify new therapeutic avenues for prostate cancer, which is the most frequently diagnosed cancer in the Western world and the leading cause of cancer-related death in men over 65 years of age. Our research provides compelling evidence to support further studies investigating the potential of sonlicromanol as an anti-tumour drug in prostate and other human cancers.”
A link to the study – Jiang, X., Renkema, H., Smeitink, J., Beyrath J. Sonlicromanol’s active metabolite KH176m normalizes prostate cancer stem cell mPGES-1 overexpression and inhibits cancer spheroid growth. PLoS ONE 16(7): e0254315 (2021) – can be found here: https://doi.org/10.1371/journal.pone.0254315
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Prof. Dr. Jan Smeitink, CEO
Consilium Strategic Communications
Mary-Jane Elliott, David Daley, Melissa Gardiner
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Khondrion is a privately held clinical-stage biopharmaceutical company discovering and developing therapies targeting mitochondrial disease. Founded by Prof. Jan Smeitink, a world-leader in mitochondrial medicine, the company is advancing its proprietary science through a wholly-owned clinical and preclinical small molecule pipeline of potential medicines.
The company’s in-house discovery engine is using unique live-cell imaging technologies, patient-derived cell lines and predictive cell-based disease models to build a portfolio of promising compounds. Active discovery programmes are underway developing new therapies, biomarkers and new read-out technologies in the field of mitochondrial diseases.
To accelerate the discovery and development of its potential medicines for mitochondrial diseases, Khondrion collaborates with a global clinical and academic network and patient organisations internationally. Khondrion is headquartered in Nijmegen, The Netherlands. For more information visit www.khondrion.com
About mitochondrial disease
Mitochondrial disease occurs when mitochondria, found within all cells of the human body and responsible for producing the energy necessary for cells to function, are defective. This can result in a wide range of serious and debilitating illnesses occuring shortly after birth or later in life. Signs and symptoms of these can include: cognitive problems, learning disabilities, blindness, deafness, heart failure, diabetes, fatigue, intolerance to exercise, muscle weakness and gait problems, and stunted growth. Orphan diseases of the oxidative phosphorylation system like Leigh disease, MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) spectrum disorders including MIDD (maternally inherited diabetes and deafness), LHON (Leber’s hereditary optic neuropathy) and other respiratory chain/ oxidative phosphorylation disorders, are all examples of mitochondrial disease.