The Promise of Modulating Lipid-Signaling Pathways
Emerging science suggests that modulating lipid-signaling pathways can unlock novel therapeutic strategies for diseases and medical conditions for which there are no or limited options. Artelo Biosciences is at the forefront of advancing the application of lipid-modulating therapeutics.
Lipids are critical to certain cell signaling pathways. Lipid-signaling modulation is the alteration of the signaling of lipid molecules to change biological activity or function within cellular communication pathways.
Lipids contain various fatty acids as their building blocks and are the key components of lipid activity. Omega-3 Fatty Acids are a commonly known example of fatty acids with proven biologic activity. Fatty Acid Binding Proteins (FABPs) facilitate lipid-signaling by binding to fatty acids which control various cellular functions. FABPs are essential mediators of normal cell signaling processes and under certain conditions can be associated with dysfunctional signaling. Inhibition of specific FABPs may correct abnormal lipid-signaling which holds promise as new treatment modalities.
Artelo’s innovative approach targets acute and chronic conditions, including pain, cancer, anxiety, depression and other conditions through modulating lipid-signaling pathways.
Learn more about lipid-signaling modulation
Understanding the Language of Lipids
Lipids are fats and oils which play crucial roles as building blocks, signaling molecules, energy sources, antioxidants, and barriers within cells. Lipids are involved in many physiologic activities and lipidomics is the study of the complete set of lipids within a cell, tissue, or organism. By analyzing the lipidome, valuable insights are gained into lipid signaling pathways in both healthy and disease states.
Cellular Messengers – Lipids transmit messages within and between cells in different ways.
- Lipid mediators, such as endocannabinoids, are lipid-based neurotransmitters that modulate a wide range of physiologic functions, including pain, appetite, mood, and memory.
- Lipids, like diacylglycerol (DAG), are pivotal secondary messengers that are generated in response to extracellular stimuli such as neurotransmitters. They orchestrate intracellular cascades triggering various cellular responses.
- Hormones synthesized from cholesterol regulate diverse physiological functions including reproduction, metabolism, and stress response.
- Certain lipid-derived molecules, such as growth factors, stimulate cell proliferation and differentiation.
Diverse Roles – Lipids are essential components of living organisms. They serve a variety of crucial functions beyond signaling within cells and the body as a whole.
- Structural Components – Phospholipids form the primary structure of cell membranes and organelle membranes, creating a barrier between the inside and outside of the cell or organelle.
- Energy Storage – Triglycerides are the primary energy storage molecules in the body and provide a concentrated source of energy. Fatty acids derived from triglycerides can be broken down to generate Adenosine Triphosphate (ATP), the energy currency of cells.
Abnormal Function – When lipid-signaling pathways are disrupted or dysfunctional, cells may not receive the proper signals to function correctly. This can lead to impaired growth, proliferation, and metabolic processes manifesting in several disease states.
- Cancer – Increased lipid metabolism and signaling can contribute to uncontrolled cell growth and proliferation, a hallmark of cancer. Inflammation – Chronic inflammation can be triggered by dysregulated lipid signaling, leading to various inflammatory diseases.
- Metabolic Disorders – Dysregulation of lipid metabolism can contribute to conditions like obesity, type 2 diabetes, and fatty liver disease.
- Cardiovascular Disease – Abnormal cholesterol levels and altered lipid signaling in blood vessels can promote atherosclerosis, a buildup of plaque that increases the risk of heart attack and stroke.
- Neurodegenerative Diseases – Dysregulation of lipid signaling in the brain has been implicated in the development of Alzheimer’s disease and Parkinson’s disease.
Fatty Acid Binding Proteins (FABPs)
FABPs are a family of intracellular lipid-binding proteins that regulate the transport and metabolism of fatty acids and lipids within cells. There are ten known FABP isoforms in humans (FABP1 through FABP9 and FABP12),1 Dysregulation of FABPs can lead to excessive lipid binding and contribute to disease states.
Therapeutic Potential of FABP Inhibitors
FABP inhibition has been identified as a novel mechanism of action to address a wide range of disease states, including metabolic disorders, inflammatory diseases, neurodegenerative diseases, and cancer. Artelo is a leader in the development of these lipidome-altering agents, holding worldwide exclusive licenses to multiple FABP inhibitors, with three patents issued in the US and 14 pending patent applications. Artelo is the first pharmaceutical company to receive FDA approval to initiate human trials with a selective FABP5 inhibitor, named ART26.12.
ART26.12: Lead FABP Inhibitor Compound
ART26.12 is a novel and selective FABP5 inhibitor from Artelo’s proprietary FABP library. In pre-clinical models, ART26.12 demonstrated efficacy in treating Chemotherapy-Induced Peripheral Neuropathy (CIPN), a debilitating complication of cancer therapies often impacting treatment strategies, including stopping treatment altogether. Similar to diabetic neuropathy, CIPN can cause intense and debilitating pain in hands and feet. There is no FDA approved treatment for CIPN.
By deciphering the language of lipids, Artelo Biosciences is on a mission to unlock transformative and novel treatments using lipid-signaling modulation to improve the lives of patients suffering from multiple diseases.
1. Smathers, R.L., Petersen, D.R. The human fatty acid-binding protein family: Evolutionary divergences and functions. Hum Genomics 5, 170 (2011). https://doi.org/10.1186/1479-7364-5-3-170
ART27.13 – Benzimidazole Derivative
ART27.13 is being developed as a once-a-day, orally administered, highly potent, peripherally restricted synthetic, dual G-protein-coupled receptor (GPCR) agonist, benzimidazole derivative believed to target the cannabinoid receptors CB1 and CB2, which has the potential to increase appetite, food intake and reduce muscle wasting.
What are the CB1 and CB2 receptors?
Lipid-signaling modulation can be affected via several approaches, including use of selective or non-selective agonists, partial agonists, inverse agonists, and antagonists of the cannabinoid receptors, CB1 and CB2. The CB1 receptor is distributed in brain areas associated with motor control, emotional responses, motivated behavior and energy homeostasis. In the periphery, CB1 is ubiquitously expressed in the adipose tissue, pancreas, liver, gastrointestinal tract, skeletal muscles, heart and the reproductive system. The CB2 receptor is mainly expressed in the immune system regulating its functions and is upregulated in response to tissue stress or damage in most cell types. Lipid-signaling within the endocannabinoid system (ECS) is therefore involved in pathophysiological conditions in both the central and peripheral tissues.
ART27.13 has demonstrated potential in cancer anorexia (appetite and weight loss) as well as cancer-induced muscle degeneration (cachexia) through its dual CB1 and CB2 receptor agonism. CB1 receptor activation has been shown to increase food intake, alter adipokine and satiety hormone levels, alter taste sensation, decrease lipolysis (fat break down), and increase lipogenesis (fat generation).1 In pre-clinical studies, ART27.13 has also been shown to result in protecting human muscle cells from cancer-induced muscle degeneration (cachexia) via a CB2 mediated mechanism of action.2
1. O’Sullivan SE, Yates AS, Porter RK. The Peripheral Cannabinoid Receptor Type 1 (CB1) as a Molecular Target for Modulating Body Weight in Man. Molecules. 2021 Oct 13;26(20):6178. doi: 10.3390/molecules26206178.
2. https://ir.artelobio.com/news-events/press-releases/detail/80/artelo-biosciences-reports-positive-pre-clinical-results
ART26.12 - Fatty Acid Binding Protein (FABP) Inhibition
ART26.12 is Artelo’s lead compound from a platform of inhibitors to Fatty Acid Binding Proteins (FABPs) with three patents issued in the US and 14 pending patent applications.
What are FABPs?
Hydrophobic ligands such as fatty acids serve many biological functions within the cell, including as metabolic energy sources, substrates for membranes and signaling molecules for metabolic regulation. Being insoluble, fatty acids require chaperones to bind and transfer them throughout various cellular compartments including the peroxisomes, mitochondria, endoplasmic reticulum, and nucleus. A family of highly expressed intracellular lipid-binding proteins called Fatty Acid Binding Proteins (FABPs) serve to bind with these free ligands to make their transport and dissemination throughout the cell possible. There are ten known FABP family members, or isoforms, expressed in humans (FABP1 through FABP9 and FABP12).1 These ten FABP isoforms are related to different processes within the body to varying extents, either independently or in concert. FABPs are believed to be attractive therapeutic targets as inhibiting abnormal or excess lipid-signaling is potentially significant for multiple conditions and diseases.
Artelo’s FABP platform includes a novel, selective FABP5 inhibitor ART26.12. FABP5 plays an important role in lipid signaling and is believed to be an attractive target for drug development in pain, inflammation and cancer. Extensive human biomarker and animal model data support FABP5 as an oncology target, including triple negative breast cancer and castration-resistant prostate cancer. Additionally, FABP5 inhibition may have therapeutic value in Chemotherapy-Induced Peripheral Neuropathy, also known as CIPN, a common and often painfully debilitating complication of cancer therapies, sometimes resulting in reduction or cessation of treatment. In pre-clinical models, inhibition of FABP5 using ART26.12 has demonstrated activity in analgesia, ameliorating painful the effects of CIPN, a condition for which no currently approved treatment exists.2
References
1. Smathers, R.L., Petersen, D.R. The human fatty acid-binding protein family: Evolutionary divergences and functions. Hum Genomics 5, 170 (2011). https://doi.org/10.1186/1479-7364-5-3-170
2. SE O’Sullivan, A Pereira, P Duffy, L Ruston, M Kaczocha, I Ojima and A Yates. Discovery and preclinical evaluation of a novel inhibitor of FABP5, ART26.12, effective in chemotherapy-induced pain. June 26, 2022, 32nd Annual International Cannabinoid Research Society (ICRS) Symposium
ART12.11 - Cannabidiol (CBD)-Tetramethylpyrazine (TMP) Cocrystal
ART12.11 is a proprietary cocrystal of cannabidiol (CBD) and tetramethylpyrazine (TMP) designed to improve pharmaceutical qualities of the CBD molecule. Artelo has been issued two patents covering composition-of-matter and method of use in the United States for ART 12.11, with additional pending patent applications.
What is polymorphism?
Polymorphism in pharmaceuticals refers to the ability of a solid material to exist in two or more crystalline forms. Polymorphic forms typically differ in their physicochemical properties and exhibit differences in pharmacological properties including absorption rate and overall bioavailability. For this reason, a drug based on a specific polymorphic form or with reduced polymorphism is likely to have an improved safety and efficacy profile.
The FDA further amplifies the challenge with drug substances associated with polymorphism in their guidance to drug developers, “Polymorphic forms of a drug substance can have different chemical and physical properties, including melting point, chemical reactivity, apparent solubility, dissolution rate, optical and mechanical properties, vapor pressure, and density. These properties can have a direct effect on the ability to process and/or manufacture the drug substance and the drug product, as well as on drug product stability, dissolution, and bioavailability. Thus, polymorphism can affect the quality, safety, and efficacy of the drug product.” 1
The crystal structure of cannabidiol (CBD) has been shown to exist in different forms indicating polymorphism is inherent.2 A preparation of cannabidiol with reduced polymorphism would be anticipated to have improved pharmaceutical properties.
What is a cocrystal and how can it address polymorphism?
Engineering of the crystalline structure of drug molecules by cocrystalization is a well-developed pharmaceutical strategy of enhanced pharmaceutics. Cocrystals are defined as crystalline materials composed of two or more molecules within the same crystal lattice. Compared to other classes of solid forms, cocrystals possess particular scientific and regulatory advantages. Although polymorphisms may also occur in cocrystals, their rational design offers the opportunity to reduce polymorphism to a greater extent compared to other pharmaceutical forms. Importantly, cocrystals are viewed as patentable subject matter.3 Thus, a pharmaceutical cocrystal offers the opportunity to develop a cannabidiol-based drug product with the potential for improved safety and efficacy from a strong proprietary position in a market searching for exclusivity advantages.
Recognizing the potential advantages of cocrystals, Artelo scientists and external collaborators set about to create a novel cocrystal of cannabidiol. The team was successful and identified a structure that meets all the criteria for an attractive pharmaceutical cocrystal, including only one polymorph (no polymorphism). In 2020, the U.S. Patent and Trademark Office issued a “composition of matter” patent with claims covering the Company’s cocrystal. The U.S. patent, No. 10,604467 for “Solid Forms of Cannabidiol and Uses Thereof,” provides intellectual property protection for ART12.11 until 2038.4
Artelo’s CBD cocrystal uses the coformer, tetramethylpyrazine (TMP; also called ligustrazine). TMP is a plant-derived compound widely used in Chinese, Korean and Native American medicine in higher doses for several diseases and conditions. In a lower quantity, TMP is also approved by the European Food Safety Authority as a food flavoring with a profile of cocoa, coffee, and mocha. The median lethal dose (estimated in rats after oral administration) is very high, about 2g/kg. Because TMP has the potential of additive or synergistic effects with CBD, Artelo’s CBD cocrystal may also benefit from pharmacologic advantages over CBD alone and on top of providing Artelo with an enviable patent protected CBD product.
References
1. Andre S. Raw, Director- Division of Chemistry I FDA-CDER-Office of Generic Drugs Regulatory Consideration on Pharmaceutical Solids: Polymorphs / Salts and Cocrystals
2. Tobias Mayr, et al., Cannabidiol revisited IUCrData (2017). 2, x170276
3. Trask AJ. Molecular Pharmaceutics (2007) 4: (3) 301 – 309
4. https://ir.artelobio.com/news-events/press-releases/detail/31/artelo-biosciences-awarded-composition-of-matter-patent-for
Publications
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