RAD140(CAS 1182367-47-0), also known as Testolone, is a potent, orally bioavailable, nonsteroidal selective androgen receptor modulator (SARM) that demonstrates excellent affinity for the androgen receptor (Ki = 7 nM). RAD140 displays potent anabolic effects in rodents and non-human primates and good bioavailability. RAD140 also demonstrates neuroprotective properties in hippocampal neurons of rat kainite model.
in vitro: RAD140 demonstrates excellent affinity for the androgen receptor (Ki = 7 nM) as well as good selectivity over other steroid hormone nuclear receptors, with the closest off target receptor being the progesterone receptor (IC50 = 750 nM). RAD140 is a novel SARM with high affinity and specificity for AR, is orally available, and exhibits potent anabolic effects in rodents and nonhuman primates.
in vivo: The stability of RAD140 is high (t1/2 > 2 h) in incubations with rat, monkey, and human microsomes, and it also had good bioavailability in rats and monkeys. RAD140 is also neuroprotective using the rat kainate lesion model. RAD140 is shown to exhibit peripheral tissue-specific androgen action that largely spared prostate, neural efficacy by activation of androgenic gene regulation effects, and neuroprotection of hippocampal neurons against cell death caused by systemic administration of the excitotoxin kainate.
1. Clin Cancer Res. 2017 Dec 15;23(24):7608-7620. doi: 10.1158/1078-0432.CCR-17-0670. Epub 2017 Oct 3.
Selective Androgen Receptor Modulator RAD140 Inhibits the Growth of Androgen/Estrogen Receptor-Positive Breast Cancer Models with a Distinct Mechanism of Action.
Yu Z(1), He S(2), Wang D(2), Patel HK(2), Miller CP(2), Brown JL(2), Hattersley G(2), Saeh JC(1).
(1)Radius Health, Inc., Waltham, Massachusetts. [email protected] [email protected]
(2)Radius Health, Inc., Waltham, Massachusetts.
Purpose: Steroidal androgens suppress androgen receptor and estrogen receptor positive (AR/ER+) breast cancer cells and were used to treat breast cancer, eliciting favorable response. The current study evaluates the activity and efficacy of the oral selective AR modulator RAD140 in in vivo and in vitro models of AR/ER+ breast cancer.Experimental Design: A series of in vitro assays were used to determine the affinity of RAD140 to 4 nuclear receptors and evaluate its tissue-selective AR activity. The efficacy and pharmacodynamics of RAD140 as monotherapy or in combination with palbociclib were evaluated in AR/ER+ breast cancer xenograft models.Results: RAD140 bound AR with high affinity and specificity and activated AR in breast cancer but not prostate cancer cells. Oral administration of RAD140 substantially inhibited the growth of AR/ER+ breast cancer patient-derived xenografts (PDX). Activation of AR and suppression of ER pathway, including the ESR1 gene, were seen with RAD140 treatment. Coadministration of RAD140 and palbociclib showed improved efficacy in the AR/ER+ PDX models. In line with efficacy, a subset of AR-repressed genes associated with DNA replication was suppressed with RAD140 treatment, an effect apparently enhanced by concurrent administration of palbociclib.Conclusions: RAD140 is a potent AR agonist in breast cancer cells with a distinct mechanism of action, including the AR-mediated repression of ESR1 It inhibits the growth of multiple AR/ER+ breast cancer PDX models as a single agent, and in combination with palbociclib. The preclinical data presented here support further clinical investigation of RAD140 in AR/ER+ breast cancer patients. Clin Cancer Res; 23(24); 7608-20. ©2017 AACR.
2. Rapid Commun Mass Spectrom. 2013 Jun 15;27(11):1173-82. doi: 10.1002/rcm.6558.
Expanding sports drug testing assays: mass spectrometric characterization of the selective androgen receptor modulator drug candidates RAD140 and ACP-105.
Thevis M(1), Piper T, Beuck S, Geyer H, Schänzer W.
(1)Institute of Biochemistry-Center for Preventive Doping Research, German Sport University Cologne, Cologne, Germany. [email protected]
RATIONALE: Anabolic agents have been top-ranked for many years among statistics of adverse analytical findings compiled by the World Anti-Doping Agency (WADA). Besides archetypical anabolic-androgenic steroids (AAS), alternative substances with similar effects concerning bone and muscle anabolism have been therapeutically pursued. A prominent emerging class of drugs is the chemically heterogeneous group of selective androgen receptor modulators (SARMs), some of which have been detected in doping control samples between 2009 and 2012 despite missing clinical approval.
METHODS: In order to support the momentum of expanding the preventive and proactive measures among anti-doping laboratories, the analytical characterization of substances with misuse potential is of great importance. In the present study, the SARM drug candidates RAD140 (comprising a 5-phenyloxadiazole nucleus) and ACP-105 (bearing an N-substituted tropanol pharmacophore) were studied regarding their mass spectrometric behavior under ESI-MS(/MS) and EI-MS(/MS) conditions. Reference material was synthesized according to established protocols and dissociation pathways of RAD140 and ACP-105 were elucidated with liquid chromatography/electrospray ionization quadrupole/time-of-flight or iontrap/orbitrap and gas chromatography/electron ionization quadrupole/time-of-flight high resolution/high accuracy mass spectrometry.
RESULTS: Fragmentation pathways to diagnostic product ions of RAD140 (e.g. m/z 223 and 205 using ESI-MS/MS and m/z 421 and 349 using EI-MS/MS) and ACP-105 (such as m/z 233 and 193 or 231 and 217 for ESI-MS/MS and EI-MS/MS measurements, respectively) were proposed as substantiated by determined elemental compositions and MS(n) experiments as well as comparison to spectra of a structural analog. Notably, for the formation of the characteristic fragment ion at m/z 421 of RAD140, the comparably seldom intramolecular migration of a trimethylsilyl residue triggered by electron ionization was suggested as corroborated by all of the above-mentioned analytical means.
CONCLUSIONS: The obtained data will support future sports drug testing methods and facilitate and accelerate the implementation of this analyte and related compounds or metabolites in both GC/MS(/MS)- and LC/MS(/MS)-based routine doping control procedures.