The Future of Hair Regrowth: Part 2 – Next Generation AR Antagonists

The search for new drugs that target prostate diseases may once again lead to new treatments for androgenetic alopecia in the future.

Just as finasteride (Propecia®) was first developed as a treatment for benign prostatic hyperplasia, a new group of androgen receptor antagonists undergoing trials for prostate cancer may prove useful for treating hair loss in coming years.

Dihydrotestosterone (DHT), an androgenic hormone, is widely recognized as a key factor in the development of androgenetic alopecia. DHT's effects on hair follicles are mediated by the androgen receptor (AR). (For more information about DHT, androgen receptors, and AR antagonists, check out our previous post on the science behind anti-androgens.)

“Triple-acting” Androgen Receptor Antagonists

A collaboration between the laboratories of Charles Sawyers (Memorial Sloan-Kettering Cancer Center) and Michael Jung (UCLA) led to the discovery of two diarylthiohydantoin compounds, MDV3100 and RD162, which represent a new class of “triple-acting” AR antagonists.1

These two compounds are derivatives of RU59063, an AR antagonist originally synthesized by scientists at Roussel-UCLAF in the early 1990s.2

Out of 200 derivative compounds the Sawyers and Jung groups screened, MDV3100 and RD162 were two of the most effective inhibitors of AR activity.

Mechanism(s) of Action

MDV3100 and RD162 are unique compared to currently prescribed AR antagonists because they disrupt activity in three complementary ways:

First, they block binding of DHT to AR by occupying the ligand binding site where DHT usually binds. This first line of defense keeps the receptor from being activated by DHT that is normally produced in the body.

Second, the compounds impede movement of AR into the cell nucleus, where the receptor normally binds to DNA and regulates the expression of genes. By keeping AR in the cytoplasm, MDV3100 and RD162 physically isolate the receptor from its site of action.

Finally, they change the shape of AR and reduce its ability to interact with DNA. When the receptor binds to DNA sequences in the genome, it acts as a molecular "on/off switch" for genes that alter cellular behavior.

This third activity is critical for preventing any receptors that are already present in the nucleus from binding to DNA and regulating the expression of genes that are presumably responsible for hair loss.

MDV3100 has a higher affinity for AR and inhibits the receptor more effectively than other currently prescribed anti-androgens like bicalutamide. Initial observations in a Phase I/II clinical trial for advanced prostate cancer have shown promising results and Phase II/III trials are in progress. (Click on the image above to see a full-size version)

Proposed Use of MDV3100 for Hair Loss

The triple-acting AR antagonists MDV3100 and RD162 were first disclosed in US Patent Application No. 20070004753 as part of a series of RU59063 derivatives. While the primary focus appears to be treating prostate cancer, the patent application hints that the drug could also be used to treat androgenetic alopecia:

“Because these compounds are strong AR inhibitors, they can be used not only in treating prostate cancer, but also in treating other AR related diseases or conditions such as benign prostate hyperplasia, hair loss, and acne.”

The patent application goes on to describe how the compounds could be formulated for topical administration:

“The diarylhydantoin compounds of the invention can be formulated as pharmaceutical compositions and administered to a subject in need of treatment, for example a mammal, such as a human patient, in a variety of forms adapted to the chosen route of administration, for example, orally, nasally, intraperitoneally, or parenterally, by intravenous, intramuscular, topical or subcutaneous routes, or by injection into tissue.”

“For topical administration, the diarylhydantoin compounds may be applied in pure form. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.”

Other Next-Generation Androgen Receptor Antagonists

Another androgen receptor antagonist to watch in the future is VN/124-1, discovered at the University of Maryland School of Medicine.3

VN/124-1 appears to work on AR by a different mechanism than MDV3100: reducing the expression of AR, i.e. the number of receptor molecules available to bind DHT.

“VN/124-1 was significantly more potent than the other compounds, with nearly complete reduction of AR expression at 15 µM in LNCaP cells, and 89% in LAPC4 cells.”

“The active ingredient, such as one or more CYP17 inhibitor(s) or compositions including any active ingredients may be administered by methods known to those skilled in the art including, but not limited to, intraperitoneally, intravenously, orally, subcutaneously, intradermally, intramuscularly, intravascularly, endotracheally, intraosseously, intra-arterially, intravesicularly, intrapleurally, topically, intraventricularly, or through a lumbar puncture (intrathecally).”

Conclusions

The next generation of AR antagonists are potent inhibitors of the androgen receptor that may hold promise for treating androgenetic alopecia in the future.

However, in order to realize this potential, several hurdles must be overcome, including tests on topical absorption and systemic toxicity, side effects, and efficacy in treating androgenetic alopecia. These studies will require a significant investment of time and money, so we will likely have to wait at least a few years before we know if any of these compounds will become available as a treatment for hair loss in the future.

Stay tuned in the coming weeks for another look into The Future of Hair Regrowth when the Avacor® Hair Regrowth Blog explores the promise of RNA interference technology for treating hair loss!

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1. Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V, Wongvipat J, Smith-Jones PM, Yoo D, Kwon A, Wasielewska T, Welsbie D, Chen CD, Higano CS, Beer TM, Hung DT, Scher HI, Jung ME, Sawyers CL. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. 2009 May 8;324(5928):787-90. Link to Pubmed

2. Teutsch G, Goubet F, Battmann T, Bonfils A, Bouchoux F, Cerede E, Gofflo D, Gaillard-Kelly M, Philibert D. Non-steroidal antiandrogens: synthesis and biological profile of high-affinity ligands for the androgen receptor. J Steroid Biochem Mol Biol. 1994 Jan;48(1):111-9. Link to Pubmed

3. Handratta VD, Vasaitis TS, Njar VC, Gediya LK, Kataria R, Chopra P, Newman D Jr, Farquhar R, Guo Z, Qiu Y, Brodie AM. Novel C-17-heteroaryl steroidal CYP17 inhibitors/antiandrogens: synthesis, in vitro biological activity, pharmacokinetics, and antitumor activity in the LAPC4 human prostate cancer xenograft model. J Med Chem. 2005 Apr 21;48(8):2972-84. Link to Pubmed