SBIR-STTR Award

Acne Vulgaris is a common skin disorder that affects 80% of the population, typically teenagers and young adults. Over 50 million people in the US are affected by acne generating a $2 billion market for acne treatments, 80% of which is derived from prescription medications. Although acne is not a life threatening condition, it still has a hih psychosocial impact resulting in depression, anxiety, anger, suicidal thoughts, physical scarring and decreased quality of life. The primary causes of acne are the overproduction of sebum by sebaceous glands, hyperkeratinization of follicular epithelium, P. acnes proliferation and inflammation. Unfortunately, the molecular mechanisms of sebum regulation are not clearly understood and this has impeded the generation of safe and effective sebosuppressive therapeutics. Retinoids have been used for more than 20 years to treat severe acne and are the only approved therapy that is effective against multiple pathological processes of acne. However, because of serious concerns regarding the teratogenic properties of retinoids, their use is now part of an FDA-mandated registry program. In addition, isotretinoin has been linked to serious side effects including clinical depression, inflammatory bowel disease and sensitive skin. There is a clear need for safe and efficacious treatments that target sebum production in sebocytes. We have identified a novel compound class in a phenotypic screen for peroxisome biogenesis that inhibits sebocyte lipid biosynthesis. Initial SAR studies surrounding this parental compound are promising and justify screening the additional derivatives to establish proof-of-concept for these compounds as acne therapeutics. The aims of this phase I project are to use our existing cell-based human sebocyte screening platform, ex-vivo skin models and in vivo Syrian hamster model to identify lead compounds in this class for further development in Phase II studies.

Public Health Relevance Statement:


Public Health Relevance:
Acne Vulgaris is a common skin disorder that affects 80% of the population, including over 50 million people in the US, the majority of which are teenagers and young adults. A primary cause of acne is excess sebum production by sebocytes. Unfortunately, current treatments while effective have severe side effects, including birth defects. We have identified a novel compound class through a phenotypic screen that inhibits sebum production from human primary sebocytes. These compounds will be further developed as safe and effective acne therapeutics.

Project Terms:
Accure; Acne; Acne Vulgaris; Adverse effects; Affect; aged; analog; Anger; Animals; Anxiety; appendage; Attention; base; Biogenesis; Cell Line; Cells; Cicatrix; Congenital Abnormality; cytotoxicity; Data; density; design; Development; Dimethyl Sulfoxide; Ear structure; Epithelium; Exposure to; face skin; Feeling suicidal; Formulation; Generations; histological specimens; Human; improved; in vivo; in vivo Model; Inflammation; Inflammatory Bowel Diseases; inflammatory marker; Injury; insight; Intraperitoneal Injections; Isotretinoin; Laboratories; Lead; Life; Link; lipid biosynthesis; lipid metabolism; Major Depressive Disorder; Marketing; Mental Depression; Mesocricetus auratus; Microscopy; Modeling; Molecular; novel; Oral; Organ; Organ Model; Pathologic Processes; Penetration; Peripheral; peroxisome; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Phase; phase 2 study; Play; Population; Process; Production; programs; Property; Propionibacterium acnes; psychosocial; public health relevance; Quality of life; Registries; Regulation; Retinoic Acid Receptor; Retinoids; Role; Safety; Sales; screening; Sebaceous Glands; Sebum; Skin; skin disorder; Spironolactone; Structure-Activity Relationship; Teenagers; Testing; Therapeutic; Therapeutic Uses; Toxic effect; treatment group; Tretinoin; young adult

Acne Vulgaris is a common skin disorder that affects 80% of the population, typically teenagers and young adults. Over 50 million people in the US are affected by acne generating a $2 billion market for acne treatments, 80% of which is derived from prescription medications. Although acne is not a life-threatening condition, it still has a high psychosocial impact resulting in depression, anxiety, anger, suicidal thoughts, physical scarring and decreased quality of life. The primary causes of acne are the overproduction of sebum by sebaceous glands, hyperkeratinization of follicular epithelium, P. acnes proliferation and inflammation. Unfortunately, the molecular mechanisms of sebum regulation are not clearly understood and this has impeded the generation of safe and effective sebosuppressive therapeutics. Retinoids have been used for more than 20 years to treat severe acne and are the only approved therapy that is effective against multiple pathological processes of acne. However, because of serious concerns regarding the teratogenic properties of retinoids, their use is now part of an FDA-mandated registry program. In addition, isotretinoin has been linked to serious side effects including clinical depression, inflammatory bowel disease and sensitive skin. There is a clear need for safe and efficacious treatments that target sebum production in sebocytes. In Phase I studies we screened a novel class of compounds identified in a phenotypic screen for peroxisome biogenesis that inhibits sebocyte lipid biosynthesis. We successfully identified active molecules, developed initial structure activity relationship around a lead scaffold and demonstrated in vivo efficacy that is comparable to isotretinoin in an animal model of sebogenesis. In this Phase II application we will use a medicinal chemistry approach to expand this series of compounds using our sebocyte screening platform and in vivo models to identify multiple novel orally bioavailable small molecules for lead optimization. Using this approach, our goal is to deliver safe, effective sebum inhibitors for the treatment of acne vulgaris.

Thesaurus Terms:
Accure; Acne; Acne Vulgaris; Adverse Effects; Affect; Aged; Analog; Anger; Animal Model; Animals; Anxiety; Appendage; Attention; Base; Bioavailable; Biogenesis; Biological Assay; Biological Availability; Cells; Characteristics; Chemicals; Cicatrix; Clinical; Clinical Candidate; Commercialization; Congenital Abnormality; Cremophor; Cytotoxicity; Data; Dermal; Development; Epithelium; Exposure To; Feeling Suicidal; Fibroblasts; Future; Generations; Genotoxicity; Goals; Hamsters; High Resolution Imaging; Histological Specimens; Histological Stains; Human; Impairment; In Vitro; In Vivo; In Vivo Model; Inflammation; Inflammatory Bowel Diseases; Inflammatory Marker; Inflammatory Response; Inhibitor/Antagonist; Injury; Intellectual Property; Isotretinoin; Keratinocyte; Laboratories; Lead; Lead Optimization; Life; Link; Lipid Biosynthesis; Lobule; Major Depressive Disorder; Mental Depression; Mesocricetus Auratus; Modeling; Molecular; New Technology; Novel; Oral; Organ; Organ Model; Pathologic Processes; Peripheral; Peroxisome; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Phase 1 Study; Phenotype; Population; Pre-Clinical; Preclinical Development; Process; Production; Programs; Property; Propionibacterium Acnes; Psychosocial; Quality Of Life; Registries; Regulation; Retinoids; Safety Testing; Sales; Scaffold; Screening; Sebaceous Glands; Sebum; Secure; Series; Skin; Skin Disorder; Small Molecule; Structure-Activity Relationship; System; Teenagers; Teratogens; Testing; Therapeutic; Therapeutic Candidate; Toxic Effect; Treatment Group; Water; Young Adult;