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

Nisha M. Badders; Ane Korff; Helen C. Miranda; Pradeep K. Vuppala; Rebecca B. Smith; Brett J. Winborn; Emmanuelle R. Quemin; Bryce L. Sopher; Jennifer Dearman; James Messing; Nam Chul Kim; Jennifer Moore; Brian D. Freibaum; Anderson P. Kanagaraj; Baochang Fan; Heather Tillman; Ping Chung Chen; Yingzhe Wang; Burgess B. Freeman; Yimei Li; Hong Joo Kim; Albert R. La Spada; J. Paul Taylor

doi:10.1038/nm.4500

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

Nisha M. Badders, Ane Korff, Helen C. Miranda, Pradeep K. Vuppala, Rebecca B. Smith, Brett J. Winborn, Emmanuelle R. Quemin, Bryce L. Sopher, Jennifer Dearman, James Messing, Nam Chul Kim, Jennifer Moore, Brian D. Freibaum, Anderson P. Kanagaraj, Baochang Fan, Heather Tillman, Ping Chung Chen, Yingzhe Wang, Burgess B. Freeman, Yimei LiHong Joo Kim, Albert R. La Spada, J. Paul Taylor

Pharmacy Practice and Pharmaceutical Sciences

Research output: Contribution to journal › Article › peer-review

25 Scopus citations

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.

Original language	English (US)
Pages (from-to)	427-437
Number of pages	11
Journal	Nature Medicine
Volume	24
Issue number	4
DOIs	https://doi.org/10.1038/nm.4500
State	Published - May 1 2018

Bibliographical note

Funding Information:
We thank N. Nedelsky for editorial assistance. We thank the transgenic core facility at St. Jude for production of AR121Q transgenic mice and ARC Technical Services at St. Jude for surgical and animal care assistance. We also thank W. Denney for guidance in use of the 'PKNCA' R package. This work was supported by the Howard Hughes Medical Institute (J.P.T.), the American-Lebanese-Syrian Associated Charities (J.P.T., H.T.), NIH R01 NS053825 (J.P.T.), NIH R01 NS100023 (A.R.L.), the Muscular Dystrophy Association (A.R.L.) and the Kennedy's Disease Association (H.C.M.).

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© 2018 Nature America, Inc., part of Springer Nature. All rights reserved.

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5975249

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Badders, N. M., Korff, A., Miranda, H. C., Vuppala, P. K., Smith, R. B., Winborn, B. J., Quemin, E. R., Sopher, B. L., Dearman, J., Messing, J., Kim, N. C., Moore, J., Freibaum, B. D., Kanagaraj, A. P., Fan, B., Tillman, H., Chen, P. C., Wang, Y., Freeman, B. B., ... Taylor, J. P. (2018). Selective modulation of the androgen receptor AF2 domain rescues degeneration in spinal bulbar muscular atrophy. Nature Medicine, 24(4), 427-437. https://doi.org/10.1038/nm.4500

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, Li, Y, Kim, HJ, La Spada, AR & Taylor, JP 2018, 'Selective modulation of the androgen receptor AF2 domain rescues degeneration in spinal bulbar muscular atrophy', Nature Medicine, vol. 24, no. 4, pp. 427-437. https://doi.org/10.1038/nm.4500

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title = "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.",

author = "Badders, {Nisha M.} and Ane Korff and Miranda, {Helen C.} and Vuppala, {Pradeep K.} and Smith, {Rebecca B.} and Winborn, {Brett J.} and Quemin, {Emmanuelle R.} and Sopher, {Bryce L.} and Jennifer Dearman and James Messing and Kim, {Nam Chul} and Jennifer Moore and Freibaum, {Brian D.} and Kanagaraj, {Anderson P.} and Baochang Fan and Heather Tillman and Chen, {Ping Chung} and Yingzhe Wang and Freeman, {Burgess B.} and Yimei Li and Kim, {Hong Joo} and {La Spada}, {Albert R.} and Taylor, {J. Paul}",

note = "Funding Information: We thank N. Nedelsky for editorial assistance. We thank the transgenic core facility at St. Jude for production of AR121Q transgenic mice and ARC Technical Services at St. Jude for surgical and animal care assistance. We also thank W. Denney for guidance in use of the 'PKNCA' R package. This work was supported by the Howard Hughes Medical Institute (J.P.T.), the American-Lebanese-Syrian Associated Charities (J.P.T., H.T.), NIH R01 NS053825 (J.P.T.), NIH R01 NS100023 (A.R.L.), the Muscular Dystrophy Association (A.R.L.) and the Kennedy's Disease Association (H.C.M.). Publisher Copyright: {\textcopyright} 2018 Nature America, Inc., part of Springer Nature. All rights reserved.",

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AU - Miranda, Helen C.

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AU - Smith, Rebecca B.

AU - Winborn, Brett J.

AU - Quemin, Emmanuelle R.

AU - Sopher, Bryce L.

AU - Dearman, Jennifer

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AU - Kim, Nam Chul

AU - Moore, Jennifer

AU - Freibaum, Brian D.

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AU - Freeman, Burgess B.

AU - Li, Yimei

AU - Kim, Hong Joo

AU - La Spada, Albert R.

AU - Taylor, J. Paul

N1 - Funding Information: We thank N. Nedelsky for editorial assistance. We thank the transgenic core facility at St. Jude for production of AR121Q transgenic mice and ARC Technical Services at St. Jude for surgical and animal care assistance. We also thank W. Denney for guidance in use of the 'PKNCA' R package. This work was supported by the Howard Hughes Medical Institute (J.P.T.), the American-Lebanese-Syrian Associated Charities (J.P.T., H.T.), NIH R01 NS053825 (J.P.T.), NIH R01 NS100023 (A.R.L.), the Muscular Dystrophy Association (A.R.L.) and the Kennedy's Disease Association (H.C.M.). Publisher Copyright: © 2018 Nature America, Inc., part of Springer Nature. All rights reserved.

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

Abstract

Bibliographical note

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