Small Molecule Src-2 Antagonists as Regulators of Sertoli Cell Function and Male

类固醇受体辅激活因子是核受体的主要调节因子。具体而言，SRC-2用作 一种雄性生殖调节因子，优先在支持细胞中表达。SRC-2雄性能够 在发情期开始时产生精子，但很快就会不育。男性生育能力的丧失是由于 支持细胞功能的缺陷，这提高了有效的抗SRC-2小分子 拮抗剂（SMA）可被开发为男性避孕剂。棉酚被测试为男性 在中国约10，000名男性中使用避孕药，发现在试验剂量下耐受性良好， 在99%的情况下都是有效的抗生育药物然而，由于不可逆不孕症的风险， 高钾血症，它作为避孕药的使用被放弃。有趣的是，棉酚处理的动物 在Sertoli细胞生物学中出现缺陷，与SRC-2小鼠中观察到的缺陷惊人相似。遗传 SRC-2破坏和棉酚处理均导致畸形精子症和年龄依赖性 睾丸退化SRC-2和棉酚处理的小鼠的支持细胞积累脂质，表明 支持细胞代谢中常见的缺陷在我们实验室对SRC-2 SMI的初步筛选中， 我们已经鉴定了几种可以破坏SRC-2的共激活因子功能的棉酚衍生物。我们有 已经完成了针对SRC-1和SRC-3的SMA的高通量筛选活动， 也为SRC-2发起了类似的努力。由于SRC-2、棉酚、支持细胞之间的紧密联系， 生物学和男性不育，我们建议筛选和表征新的SRC-2 S M ^作为一类新的 男性避孕药。结合对U 54中存在的化合物化学的支持， 应用，我们希望产生SRC-2靶向的男性避孕药， 临床上可行。

The Steroid Receptor Coactivators are master regulators of nuclear receptors. Specifically, SRC-2 serves as a regulator of male reproduction and is preferentially expressed in Sertoli cells. SRC-2'^' males are able to produce sperm at tlie onset of pulserty, but quickly become infertile. This loss of male fertility is due to defects in Sertoli cell function which raises the possibility that effective anti-SRC-2 small molecule antagonists (SMAs) can be developed as male contraceptive agents. Gossypol was tested as a male contraceptive agent in ~10,000 men in China and was found to be well tolerated at the doses tested and was effective as an anti-fertility agent 99% of the time. However, due to the risic of inreversible infertility and hyperkalemia, its use as a contraceptive agent was abandoned. Interestingly, gossypol treated animals develop defects in Sertoli cell biology that are strikingly similar to that seen in SRC-2''' mice. Genetic disruption of SRC-2 and gossypol treatment both result in teratozoospermia and age dependent-iike testicular degeneration. Sertoli cells of both SRC-2''' and gossypol-treated mice accumulate lipid, indicative of a common defect in Sertoli cell metabolism. In preliminary screening for SRC-2 SMIs in our laboratory, we have identified several gossypol derivatives that can disrupt the coactivator function of SRC-2. We have already completed high throughput screening campaigns for SMAs against SRC-1 and SRC-3 and are initiating a similar effort for SRC-2 as well. Because of the strong link between SRC-2, gossypol, Sertoli cell biology and male infertility, we propose to screen and characterize new SRC-2 S M ^ as a novel class of male contraceptive agents. In conjunction with support for compound chemistry that exists in this U54 application, we expect to generate SRC-2-targeting male contraceptive agents with the potential to be clinically viable.