Preclinical pharmacology of FL442, a novel nonsteroidal androgen receptor modulator

Poutiainen, Pekka; Huhtala, Tuulia; Jääskeläinen, Tiina; Petsalo, Aleksanteri; Küblbeck, Jenni; Kaikkonen, Sanna; Palvimo, Jorma J.; Raunio, Hannu; Närvänen, Ale; Peräkylä, Mikael; Juvonen, Risto O.; Honkakoski, Paavo; Laatikainen, Reino; Pulkkinen, Juha

doi:10.1016/j.mce.2014.02.008

Cited by 3 publications

(3 citation statements)

References 44 publications

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“…Solomon et al recently reviewed two SARMs, FL442 and MK-4541, which have been tested/explored as treatments for PCa. FL442 acted as an AR antagonist in the PCa cell models with efficacy comparable to that of enzalutamide (4,58). Meanwhile, MK-4541 induced apoptosis in androgen-independent, AR-positive PCa cell lines (59).…”

Section: Pcamentioning

confidence: 97%

Selective androgen receptor modulators: the future of androgen therapy?

Christiansen

Lipshultz²,

Hotaling

et al. 2020

Transl Androl Urol

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Since their discovery near the close of the 20 th century (1), selective androgen receptor modulators (SARMs) have been heralded as the possible future of androgen therapy (2). As satisfaction, side effects, preparations, and perceptions have limited the utility of testosterone therapy (TTh), SARMs are poised to fundamentally alter the field of androgen therapy (2).SARMs are chemically engineered small molecule drugs that can selectively exert varying degrees of agonist and antagonist effects on the androgen receptor (AR) throughout the body. Like androgens, SARMs enter the cytoplasm and bind to the AR. After translocating to the nucleus, the SARM-AR complex acts as a transcriptional regulator and recruits cofactors and coregulatory proteins, modulating the transcriptional response to binding of the AR complex (3,4). While the AR is universally expressed, SARM-AR complexes can have varied effects due to variable cofactor recruitment (5). These complex configurations, along with tissue-dependent differences in AR expression patterns and regulatory milieu, allow for immense diversity of actions (4).SARMs promise novel, convenient therapies that facilitate tissue-specific benefits without off-target side effects (6). Given the myriad drawbacks of TTh that can limit its use, including currently available formulations and common adverse effects, one can understand the excitement surrounding SARMs. Although still in the early stages of

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Section: Pcamentioning

confidence: 97%

Selective androgen receptor modulators: the future of androgen therapy?

Christiansen

Lipshultz²,

Hotaling

et al. 2020

Transl Androl Urol

View full text Add to dashboard Cite

show abstract

“…recently published mouse data showing that a new SARM, FL442, reached high tissues concentrations in the prostate and acted as an AR antagonist in prostate cancer (PCa) cell models with efficacy comparable to that of enzalutamide, an antiandrogen used in the treatment of castration resistant PCa. [24] Notably, FL442 maintained the ability to prevent cell proliferation even in cell lines with AR mutations that conferred resistance to enzalutamide. [24] Likewise, work by Schmidt et al .…”

Section: Therapeutic Promise Of Sarmsmentioning

confidence: 99%

“…[24] Notably, FL442 maintained the ability to prevent cell proliferation even in cell lines with AR mutations that conferred resistance to enzalutamide. [24] Likewise, work by Schmidt et al . focused on MK-4541, which induces Caspase-3 activity and apoptosis in androgen independent AR positive prostate cancer cell lines while sparing AR- and AR + non-prostate cancer cells.…”

Section: Therapeutic Promise Of Sarmsmentioning

confidence: 99%

Selective Androgen Receptor Modulators: Current Knowledge and Clinical Applications

Solomon

Mirabal

Mazur

et al. 2019

Sexual Medicine Reviews

138

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Introduction: Selective androgen receptor modulators (SARMs) differentially bind to androgen receptors depending on each SARM’s chemical structure. As a result, SARMs result in anabolic cellular activity while avoiding many of the side effects of currently available anabolic steroids. SARMs have been studied in the treatment of breast cancer and cachexia and have also been used as performance enhancing agents. Here, we evaluate and summarize the current literature on SARMs. Aims: To present the background, mechanisms, current and potential clinical applications, as well as risks and benefits of SARMs. Methods: A literature review was performed in MEDLINE using the terms selective androgen receptor modulator, hypogonadism, cachexia, breast cancer, benign prostatic hyperplasia, libido and lean muscle mass. Both basic research and clinical studies were included. Results: While there are currently no FDA-approved indications for SARMs, investigators are exploring the potential uses for these compounds. Basic research has focused on the pharmacokinetics and pharmacodynamics of these agents, demonstrating good availability with a paucity of drug interactions. Early clinical studies have demonstrated potential uses for SARMs in the treatment of cancer-related cachexia, benign prostatic hyperplasia, hypogonadism, and breast cancer, with positive results. Conclusion: SARMs have numerous possible clinical applications, with promise for the safe use in the treatment of cachexia, BPH, hypogonadism, breast cancer, and prostate cancer.

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