A Targeted Bivalent Androgen Receptor Binding Compound for Prostate Cancer Therapy
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The androgen-directed treatment of prostate cancer (PCa) is fraught with the recurrent profile of failed treatment due to drug resistance and must be addressed if we are to provide an effective therapeutic option. The most singular difficulty in the treatment of PCa is the failure to respond to classical androgen withdrawal or androgen blockade therapy, which often develops as the malignancy incurs genetic alterations and gain-of-function somatic mutations in the androgen receptor (AR). Physical cellular damaging therapeutic agents, such as radiation or activatable heat-generating transducers would circumvent classical “anti-functional” biological resistance, but to become ultimately effective would require directed application modalities. To this end, we have developed a novel AR-directed therapeutic agent by creating bivalent androgen hormone-AF-2 compounds that bind with high affinity to AR within cells. Here, we used molecular modeling and synthetic chemistry to create a number of compounds by conjugating 5α-dihydrotestosterone (DHT) to various AF-2 motif sequence peptides, through the use of a glycine and other spacer linkers. Our data indicates these compounds will bind to the AR in vitro and that altering the AF-2 peptide composition of the compound does indeed improve affinity for the AR. We also show that many of these bivalent compounds can readily pass through the plasma membrane and effectively compete against androgens alone.
KeywordsAndrogen receptor Prostate cancer Androgen Bivalent compound AF-2 domain Therapeutics Molecular dynamics simulation
The work was supported by a grant from Prostate Cancer Canada/Movember Foundation—Pilot Grant (#2012-905). Salary support for S.C. was provided by The Department of Urology—Jewish General Hospital (Montreal, Canada).
. SPEP-24 trajectory of the 50 ns MD simulation in explicit water. (MP4 29559 kb)
- 5.DePriest AD et al (2016) Regulators of androgen action resource: a one-stop shop for the comprehensive study of androgen receptor action. DatabaseGoogle Scholar
- 8.He B, Gampe RT Jr, Kole AJ, Hnat AT, Stanley TB, An G, Stewart EL, Kalman RI, Minges JT, Wilson EM (2004) Structural basis for androgen receptor interdomain and coactivator interactions suggests a transition in nuclear receptor activation function dominance. Mol Cell 16(3):425–438CrossRefGoogle Scholar
- 16.Robinson D, van Allen EM, Wu YM, Schultz N, Lonigro RJ, Mosquera JM, Montgomery B, Taplin ME, Pritchard CC, Attard G, Beltran H, Abida W, Bradley RK, Vinson J, Cao X, Vats P, Kunju LP, Hussain M, Feng FY, Tomlins SA, Cooney KA, Smith DC, Brennan C, Siddiqui J, Mehra R, Chen Y, Rathkopf DE, Morris MJ, Solomon SB, Durack JC, Reuter VE, Gopalan A, Gao J, Loda M, Lis RT, Bowden M, Balk SP, Gaviola G, Sougnez C, Gupta M, Yu EY, Mostaghel EA, Cheng HH, Mulcahy H, True LD, Plymate SR, Dvinge H, Ferraldeschi R, Flohr P, Miranda S, Zafeiriou Z, Tunariu N, Mateo J, Perez-Lopez R, Demichelis F, Robinson BD, Schiffman M, Nanus DM, Tagawa ST, Sigaras A, Eng KW, Elemento O, Sboner A, Heath EI, Scher HI, Pienta KJ, Kantoff P, de Bono JS, Rubin MA, Nelson PS, Garraway LA, Sawyers CL, Chinnaiyan AM (2015) Integrative clinical genomics of advanced prostate cancer. Cell 161(5):1215–1228CrossRefGoogle Scholar
- 21.Gottlieb B et al (2012) The androgen receptor gene mutations database: 2011 update. Hum MutatGoogle Scholar
- 23.Korpal M, Korn JM, Gao X, Rakiec DP, Ruddy DA, Doshi S, Yuan J, Kovats SG, Kim S, Cooke VG, Monahan JE, Stegmeier F, Roberts TM, Sellers WR, Zhou W, Zhu P (2013) An F876L mutation in androgen receptor confers genetic and phenotypic resistance to MDV3100 (enzalutamide). Cancer discovery 3(9):1030–1043CrossRefGoogle Scholar
- 25.Wilt TJ, Brawer MK, Jones KM, Barry MJ, Aronson WJ, Fox S, Gingrich JR, Wei JT, Gilhooly P, Grob BM, Nsouli I, Iyer P, Cartagena R, Snider G, Roehrborn C, Sharifi R, Blank W, Pandya P, Andriole GL, Culkin D, Wheeler T (2012) Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med 367(3):203–213CrossRefGoogle Scholar
- 26.Bill-Axelson A, Holmberg L, Filen F, Ruutu M, Garmo H, Busch C, Nordling S, Haggman M, Andersson SO, Bratell S, Spangberg A, Palmgren J, Adami HO, Johansson JE, for the Scandinavian Prostate Cancer Group Study Number 4 (2008) Radical prostatectomy versus watchful waiting in localized prostate cancer: the Scandinavian prostate cancer group-4 randomized trial. J Natl Cancer Inst 100(16):1144–1154CrossRefGoogle Scholar
- 44.Agoulnik IU, Weigel NL (2008) Androgen receptor coactivators and prostate cancer. Horm Carci V 617:245–255Google Scholar
- 51.Artursson P (1998) Application of physiochemical properties of molecules to predict intestinal permeability. In Proceedings of the AAPS Workshop on Permeability Definitions and Regulatory Standards. Arlington, VAGoogle Scholar