title: Inhibition of Sebum Production with the Acetyl Coenzyme A Carboxylase Inhibitor Olumacostat Glasaretil.
abstract: Olumacostat glasaretil (OG) is a small molecule inhibitor of acetyl coenzyme A (CoA) carboxylase (ACC), the enzyme that controls the first rate-limiting step in fatty acid biosynthesis. Inhibition of ACC activity in the sebaceous glands is designed to substantially affect sebum production, because over 80% of human sebum components contain fatty acids. OG inhibits de novo lipid synthesis in primary and transformed human sebocytes. TrueMass Sebum Panel analyses showed a reduction in saturated and monounsaturated fatty acyl chains across lipid species, including di- and triacylglycerols, phospholipids, cholesteryl esters, and wax esters in OG-treated sebocytes. There was no shift to shorter acyl chain lengths observed, suggesting that the fatty acid chain elongation process was not affected. OG is a pro-drug of the ACC inhibitor 5-(tetradecyloxy)-2-furoic acid and was designed to enhance delivery in vivo. Topical application of OG but not 5-(tetradecyloxy)-2-furoic acid significantly reduced hamster ear sebaceous gland size, indicating that this pro-drug approach was critical to obtain the desired activity in vivo. High-performance liquid chromatography analyses of hamster ear extracts showed that OG treatment increased ACC levels and the ratio of acetyl-CoA to free CoA in these animals, indicating increased fatty acid oxidation. These changes are consistent with ACC inhibition. Matrix-assisted laser desorption/ionization imaging showed that OG applied onto Yorkshire pig ears accumulated in sebaceous glands relative to the surrounding dermis. Sebaceous gland ACC represents an attractive therapeutic target given its central role in formation of sebum, a key factor in acne pathogenesis.
authors.affiliation: Dermira, Inc., Menlo Park, California, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Hunt
authors.affiliation: Zymeworks, Vancouver, British Columbia, Canada.
authors.forename: Geoffrey C
authors.initials: GC
authors.lastname: Winters
authors.affiliation: Department of Biochemistry and Molecular Biology and the Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Roger W
authors.initials: RW
authors.lastname: Brownsey
authors.affiliation: Department of Biochemistry and Molecular Biology and the Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Jerzy E
authors.initials: JE
authors.lastname: Kulpa
authors.affiliation: Department of Dermatology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA.
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Gilliland
authors.affiliation: Department of Dermatology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA.
authors.forename: Diane M
authors.initials: DM
authors.lastname: Thiboutot
authors.affiliation: Dermira, Inc., Menlo Park, California, USA. Electronic address: hans.hofland@dermira.com.
authors.forename: Hans E
authors.initials: HE
authors.lastname: Hofland
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors*; D000152:Acne Vulgaris / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000279:Administration, Cutaneous; D000818:Animals; D006224:Cricetinae; D004195:Disease Models, Animal; D006801:Humans; D007641:Keratolytic Agents / Q000008:administration & dosage; D011355:Prodrugs; D012627:Sebaceous Glands / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D012629:Sebum / Q000187:drug effects* / Q000378:metabolism; D014212:Tretinoin / Q000008:administration & dosage*
chemical_list: D007641:Keratolytic Agents; D011355:Prodrugs; D014212:Tretinoin; D000103:Acetyl-CoA Carboxylase