title: An assessment of the genetic toxicology of novel boron-containing therapeutic agents.
abstract: Boron-containing compounds are being studied as potential therapeutic agents. As part of the safety assessment of these therapeutic agents, a battery of genetic toxicology studies was conducted. The battery included a bacterial reverse mutation (Ames) assay, an in vitro chromosome aberration assay in peripheral human lymphocytes, and an in vivo rat micronucleus study. The following compounds represent some of the boron-containing compounds that have been advanced to human clinical trials in various therapeutic areas. The borinic picolinate, AN0128, is an antibacterial compound with anti-inflammatory activity that has been studied in clinical trials for acne and the treatment of mild to moderate atopic dermatitis. AN2690 (tavaborole) is a benzoxaborole in Phase 3 clinical trials for the topical treatment of onychomycosis, a fungal infection of the toenails and fingernails. Another benzoxaborole derivative, AN2728, a phosphodiesterase-4 (PDE4) inhibitor, is in Phase 2 clinical trials for the treatment of atopic dermatitis. AN2898, also a PDE4 inhibitor, has been studied in clinical trials for atopic dermatitis and psoriasis. AN3365 is a leucyl-tRNA synthetase inhibitor that has been in clinical development for the treatment of various Gram-negative bacterial infections. These five representative compounds were negative in the three genotoxicity assays. Furthermore, AN2690 has been studied in mouse and rat 2-year bioassays and was not found to have any carcinogenic potential. These results demonstrate that it is possible to design boron-based therapeutic agents with no genetic toxicology liabilities.
authors.affiliation: Anacor Pharmaceuticals, Inc., 1020 East Meadow Circle, Palo Alto, California 94303-4230, USA. vciaravino@anacor.com
authors.forename: Vic
authors.initials: V
authors.lastname: Ciaravino
authors.forename: Jacob
authors.initials: J
authors.lastname: Plattner
authors.forename: Sanjay
authors.initials: S
authors.lastname: Chanda
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity; D000935:Antifungal Agents / Q000633:toxicity; D001880:Boranes / Q000633:toxicity; D001896:Boron Compounds / Q000633:toxicity*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000633:toxicity; D002478:Cells, Cultured; D004247:DNA / Q000187:drug effects*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D015162:Micronucleus Tests; D015394:Molecular Structure; D009152:Mutagenicity Tests; D011725:Pyridines / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C515885:3-hydroxypyridine-2-carbonyloxy-bis(3-chloro-4-methylphenyl)borane; D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D001880:Boranes; D001896:Boron Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D011725:Pyridines; D004247:DNA; C512998:tavaborole; C543085:crisaborole