Drug Discovery Department, Moffitt Cancer Center, Tampa, Florida 33612, USA.
Prostate. 2010 Sep 1;70(12):1274-85. doi: 10.1002/pros.21163.
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.
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.
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.
Ack1 Tyr284 phosphorylation is prognostic of progression of prostate cancer and inhibitors of Ack1 activity could be novel therapeutic agents to treat AIPC.
雄激素受体（AR）在雄激素依赖性和雄激素非依赖性前列腺癌（AIPC）的进展中起着关键作用。AIPC 或去势抵抗性前列腺癌（CRPC）中 AR 的配体非依赖性激活通常与预后不良有关。最近，酪氨酸激酶 Ack1 已被证明通过磷酸化 AR 的酪氨酸 267 来调节 AR 活性，这一事件对于 AIPC 的生长至关重要。然而，是否存在能够减轻 Ack1 激活的小分子抑制剂足以在去雄激素环境中消除 AR 活性调节的 AR 启动子上的 AR 活性尚不清楚。
我们已经生成了两个关键资源，即特异性识别 pTyr267-AR 的抗体和 Ack1 的小分子抑制剂 4-氨基-5,6-双芳基呋喃并[2,3-d]嘧啶（在这里命名为 AIM-100），以测试 AIM-100 是否调节配体非依赖性 AR 活性并抑制前列腺细胞生长。
前列腺组织微阵列分析表明，Ack1 Tyr284 磷酸化与疾病进展呈正相关，与前列腺癌患者的生存呈负相关。有趣的是，在激活的 Ack1 表达或 EGF 刺激的前列腺细胞中，抗雄激素既不影响 pTyr267-AR 的表达，也不影响其转录激活。然而，Ack1 抑制剂 AIM-100 不仅抑制 Ack1 激活，还能抑制 pTyr267-AR 磷酸化、AR 与 PSA、NKX3.1 和 TMPRSS2 启动子的结合以及 AR 转录活性。
Ack1 Tyr284 磷酸化是前列腺癌进展的预后标志物，Ack1 活性抑制剂可能是治疗 AIPC 的新型治疗剂。
