Abstract:
:Spinal bulbar muscular atrophy (SBMA) is a motor neuron disease caused by toxic gain of function of the androgen receptor (AR). Previously, we found that co-regulator binding through the activation function-2 (AF2) domain of AR is essential for pathogenesis, suggesting that AF2 may be a potential drug target for selective modulation of toxic AR activity. We screened previously identified AF2 modulators for their ability to rescue toxicity in a Drosophila model of SBMA. We identified two compounds, tolfenamic acid (TA) and 1-[2-(4-methylphenoxy)ethyl]-2-[(2-phenoxyethyl)sulfanyl]-1H-benzimidazole (MEPB), as top candidates for rescuing lethality, locomotor function and neuromuscular junction defects in SBMA flies. Pharmacokinetic analyses in mice revealed a more favorable bioavailability and tissue retention of MEPB compared with TA in muscle, brain and spinal cord. In a preclinical trial in a new mouse model of SBMA, MEPB treatment yielded a dose-dependent rescue from loss of body weight, rotarod activity and grip strength. In addition, MEPB ameliorated neuronal loss, neurogenic atrophy and testicular atrophy, validating AF2 modulation as a potent androgen-sparing strategy for SBMA therapy.
journal_name
Nat Medjournal_title
Nature medicineauthors
Badders NM,Korff A,Miranda HC,Vuppala PK,Smith RB,Winborn BJ,Quemin ER,Sopher BL,Dearman J,Messing J,Kim NC,Moore J,Freibaum BD,Kanagaraj AP,Fan B,Tillman H,Chen PC,Wang Y,Freeman BB III,Li Y,Kim HJ,La Spada ARdoi
10.1038/nm.4500subject
Has Abstractpub_date
2018-05-01 00:00:00pages
427-437issue
4eissn
1078-8956issn
1546-170Xpii
nm.4500journal_volume
24pub_type
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