title: Effect of Ack1 tyrosine kinase inhibitor on ligand-independent androgen receptor activity.
abstract: BACKGROUND
  Androgen receptor (AR) plays a critical role in the progression of both androgen-dependent and androgen-independent prostate cancer (AIPC). Ligand-independent activation of AR in AIPC or castration resistant prostate cancer (CRPC) is often associated with poor prognosis. Recently, tyrosine kinase Ack1 has been shown to regulate AR activity by phosphorylating it at tyrosine 267 and this event was shown to be critical for AIPC growth. However, whether a small molecule inhibitor that can mitigate Ack1 activation is sufficient to abrogate AR activity on AR regulated promoters in androgen-depleted environment is not known.
  
  
  METHODS
  We have generated two key resources, antibodies that specifically recognize pTyr267-AR and synthesized a small molecule inhibitor of Ack1, 4-amino-5,6-biaryl-furo[2,3-d]pyrimidine (named here as AIM-100) to test whether AIM-100 modulates ligand-independent AR activity and inhibits prostate cell growth.
  
  
  RESULTS
  Prostate tissue microarray analysis indicates that Ack1 Tyr284 phosphorylation correlates positively with disease progression and negatively with the survival of prostate cancer patients. Interestingly, neither pTyr267-AR expression nor its transcriptional activation was affected by anti-androgens in activated Ack1 expressing or EGF stimulated prostate cells. However, the Ack1 inhibitor, AIM-100, not only inhibited Ack1 activation but also able to suppress pTyr267-AR phosphorylation, binding of AR to PSA, NKX3.1, and TMPRSS2 promoters, and inhibit AR transcription activity.
  
  
  CONCLUSIONS
  Ack1 Tyr284 phosphorylation is prognostic of progression of prostate cancer and inhibitors of Ack1 activity could be novel therapeutic agents to treat AIPC.
authors.affiliation: Drug Discovery Department, Moffitt Cancer Center, Tampa, Florida 33612, USA.
authors.forename: Kiran
authors.initials: K
authors.lastname: Mahajan
authors.forename: Sridevi
authors.initials: S
authors.lastname: Challa
authors.forename: Domenico
authors.initials: D
authors.lastname: Coppola
authors.forename: Harshani
authors.initials: H
authors.lastname: Lawrence
authors.forename: Yunting
authors.initials: Y
authors.lastname: Luo
authors.forename: Harsukh
authors.initials: H
authors.lastname: Gevariya
authors.forename: Weiwei
authors.initials: W
authors.lastname: Zhu
authors.forename: Y Ann
authors.initials: YA
authors.lastname: Chen
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Lawrence
authors.forename: Nupam P
authors.initials: NP
authors.lastname: Mahajan
mesh_terms: D000595:Amino Acid Sequence; D000728:Androgens / Q000235:genetics / Q000502:physiology*; D000818:Animals; D000917:Antibody Formation; D045744:Cell Line, Tumor; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D010748:Phosphopeptides / Q000737:chemistry; D011470:Prostatic Hyperplasia / Q000150:complications; D011471:Prostatic Neoplasms / Q000235:genetics / Q000401:mortality / Q000503:physiopathology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011817:Rabbits; D011944:Receptors, Androgen / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D015996:Survival Rate
chemical_list: D000728:Androgens; D010748:Phosphopeptides; D011944:Receptors, Androgen; D011505:Protein-Tyrosine Kinases; C403262:TNK2 protein, human