Selective modulation of the androgen receptor AF2 domain rescues degeneration in spinal bulbar muscular atrophy.

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 Med

journal_title

Nature medicine

authors

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 AR

doi

10.1038/nm.4500

subject

Has Abstract

pub_date

2018-05-01 00:00:00

pages

427-437

issue

4

eissn

1078-8956

issn

1546-170X

pii

nm.4500

journal_volume

24

pub_type

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