1.Introduction
2.Patented AR antagonists
3.Conclusions
4.
Expert
opinion
Review
Androgen receptor antagonists:a patent review (2008--2011)
Michael L Mohler,Christopher C Coss,Charles B Duke III,Shivaputra A Patil,Duane D Miller &James T Dalton †
†
Preclinical Research and Development,GTx,Inc.,Memphis,TN,USA
Introduction:Androgen receptor (AR)antagonists are predominantly used as chemical castration to treat prostate cancer (i.e.,in conjunction with androgen deprivation therapy (ADT)).Unfortunately,castration-resistant prostate cancer (CRPC)typically develops that is refractory to targeted therapy.Insights into CRPC biology have led to the emergence of a promising clinical candidate MDV3100(1)and a resurgence in this field.A pipeline of preclinical competitive 1.1
The androgen receptor as a pharmacological target 1.1.1AR signaling
The androgen receptor (AR)is a member of the nuclear hormone receptor family and functions as a ligand-activated transcription factor in diverse tissues throughout the body [1].The AR shares greatest sequence homology with the progesterone (PR),glucocorticoid (GR),mineralocorticoid (MR)and estrogen (ER)receptors having 80--90%of DNA-binding domain (DBD)amino acid sequence in common but differing in the ligand-binding domain (LBD)by as much as 49%and thus permit-ting differential ligand recognition.Unliganded or apo-AR resides in the cytoplasm bound by heat-shock proteins,held in an inactive state.Accepted models of classic AR action suggest that upon ligand binding,the receptor translocates to the nucleus,homo-dimerizes and binds specific DNA sequences known as androgen response elements (AREs)in the promoter or enhancer region of target genes resulting in changes in gene expression [2].Growing evidence also supports a rapid signaling role for the AR whereby androgen-mediated effects are detected in an amount of time insufficient for de novo RNA synthesis (seconds)[3,4].These non-genomic
10.1517/13543776.2012.682571©2012Informa UK,Ltd.ISSN 1354-3776
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effects include direct interaction with critical intracellular effectors such as phosphoinositide 3-kinase (PI3K)and the tyrosine kinase SRC [5,6].Though ubiquitously expressed,AR signaling is tightly controlled in a temporal and spatial manner by many factors.These include modulation of local ligand concentration and bioactivation,co-regulator expres-sion,chromatin structure and input from numerous kinase signaling cascades [3,7].
1.1.2
Modular nature of the AR
Structurally,the AR is a modular protein made up of discrete functional domains working in concert to affect androgen signaling (Figure 1).The amino-terminal of the AR,or N-terminal domain (NTD),is both necessary and sufficient for AR-mediated transcription [8].The NTD contains several well-characterized transcription co-regulator interac-tion domains that afford its recruitment and stabilization of cellular transcriptional machinery as well as a polymorphic region consisting of variable numbers of the trinucleotide (CAG,coding for glutamine)repeats [3,9].The number of repeats is inversely related to AR activity and associated with a spectrum of androgen insensitivity diseases.The NTD is also known to contact the carboxy-terminal LBD when an agonist is bound,creating intra-and intermolecular AR N --C interactions that play critical roles in both the nuclear shuttling and transcriptional capacity of the receptor [10,11].Critical ‘FxxLF’and ‘WxxLF’motifs in the AR-NTD mimic the ‘LxxLL’nuclear receptor box motif found in many co-regulators,facilitating competition for AF2-binding between AR-NTD and co-regulator elements [12].The highly conserved DBD contains two zinc fingers oriented such that the AR recognizes inverted repeated nucleic acid sequences primarily in the regulatory regions of target genes [13].The
similarity and promiscuity of response elements among related receptors suggest that response elements are minimally involved in signal specificity [3].However,variability in ARE sequence has been shown to dictate critical allosteric interactions such as head-to-head versus head-to-tail homodi-merization [14].Between the DBD and the C-terminal LBD lies the hinge region containing the nuclear localization signal (NLS).The NLS contains two clusters of basic amino acids that permit its interaction with cytoskeletal components upon ligand binding [15].Recently,the hinge region has also been found to serve as an integrator for signals coming from different pathways that provide feedback to the control of AR activity [16].The LBD is the carboxy-terminal domain of the AR and the nexus of androgen signa-ling.When bound to endogenous ligands,conformational changes in the LBD stabilize the ligand --receptor complex via charge-clamp,this in turn facilitates the aforementioned N --C interaction and provides additional co-regulator binding domains [17,18].Whereas the NTD is required for transcrip-tion,several active AR splice variants lacking the LBD have been described [19,20].
1.1.3
AR physiology
Androgen signaling initiates early in fetal development and is responsible for male sexual differentiation.Production of the predominant circulating androgen testosterone (T)is detectable in the 8th week of male embryo development and will ulti-mately rise to adult levels during pubertal development [1].T is primarily produced by the Leydig cells in the testis but is also synthesized in the adrenal cortex,liver and in the female ovary [17].Testosterone can be reduced to the more potent androgen 5a -dihydrotestosterone (DHT)or aromatized to estradiol in a tissue-specific manner depending on the required endocrine signal [21].AR tissue expression is strongly correlated with androgen sensitivity,which is readily apparent in accessory sexual tissues [22].Hershberger et al.performed classical studies whereby male rats were castrated and changes in androgen-dependent tissues monitored.These models,still very much in use today,served to characterize androgen physiology and as a platform to study the effects of exogenous androgen administration [23,24].Androgen withdrawal produces declines in anabolic (muscle and bone mass)and androgenic (size of epididymis,vas deferens and prostate)features.Androgenic processes supported by AR signaling include the development,growth and support of male primary sexual characteristics,as well as exerting influence on secondary gender dimorphic sexual characteristics such as body conformation (bone and muscle mass),skin quality,hair distribution and adipose tissue,while also required for their proper homeostasis regardless of sex [21,25-27].Knockout mouse models suggest critical functions in follicular maturation,female fertility and brain patterning and activation driving sexual behavior as well [27,28].With such critical roles in numerous physiological processes,it follows that dysfunctional androgen signaling is implicated in disease.
Article highlights.
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The role of the androgen receptor (AR)in prostate
cancers including castration-resistant prostate cancer has been confirmed,spurring resurgence in the field of AR antagonism.
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Recent AR antagonists have been used to discover novel mechanisms of AR action,providing information-rich screening paradigms and novel design targets.
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C-terminally targeted competitive antagonists are now often screened as nuclear translocation inhibitors,selective AR downregulators or degraders (SARDs),antagonists of wild-type and escape mutant ARs (pan-antagonists),and/or antagonists of AR target organs in vivo .
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Despite challenges in compound design,N-terminally targeted noncompetitive antagonists with promising preclinical profiles have been reported.
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The advances in AR biology and the emergence of a promising clinical candidate (MDV3100(1))suggest that novel therapeutics targeting the AR are coming.
This box summarizes key points contained in the article.
M.L.Mohler et al .
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E x p e r t O p i n . T h e r . P a t e n t s D o w n l o a d e d f r o m i n f o r m a h e a l t h c a r e .c o m b y S e r i a l s U n i t - L i b r a r y o n 01/14/13
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