Peptide-based conjugate for a water-insoluble drug treating advanced prostate cancer

磷脂酰肌醇3-激酶(PI3Ks)信号通路是细胞周期调控中最重要的信号通路之一。 癌症，以及一些PI3K抑制剂目前正在进行临床前和临床研究 各种癌症疗法。我们和其他人已经证明了异构体PI3K-P100β是 对前列腺癌的肿瘤发生和雄激素非依赖性进展至关重要。TGX-221是一种 PI3K-P100β的新型、异构体特异性和有效的小分子抑制物。而TGX-221， 因此，具有相当大的潜力作为一种新型的前列腺癌化疗药物，其不足 前列腺癌细胞的溶解性和缺乏选择性限制了其临床应用。我们 最近合成了一种TGX-221衍生物TGX-D1，它含有一个羟基，用于 多肽结合，但表现出与TGX-221相似的活性和异构体特异性。在这 项目中，我们将TGX-D1的-OH替换为-SH，形成TGX-SH，它将有更好的 血清中的稳定性。 本项目的总体目标是：1)开发一种新型的多肽修饰的TGX-SH以 克服TGX-221的两个潜在障碍，即溶解性差和缺乏特异性 前列腺癌细胞；2)评价其联合其他药物的治疗效果。 抗前列腺癌药物。该项目的长期目标是开发一种基于多肽的 该平台不仅可用于TGX-SH，还可用于其他抗前列腺癌药物 溶解性差，组织特异性差。 在药物发现中，大约40%的新化学实体是亲脂性的，无法到达 由于溶解性差而进入市场。更不用说缺乏组织特异性是另一个主要原因 对大多数化学实体来说都是一个挑战。成功完成建议的研究或可提供 对于其他面临类似临床挑战的小分子药物来说，前景看好 稳定性差，打靶能力不足。

The phosphoinositide 3-kinases (PI3Ks) signaling pathway is one of the most important pathways in cancer, and a number of PI3K inhibitors are currently in preclinical and clinical studies for various cancer therapies. We and others have demonstrated that the isoform PI3K-p100β is essential for tumorigenesis and androgen-independent progression in prostate cancer. TGX-221 is a novel, isoform- specific, and potent small molecule inhibitor of PI3K-p100β. While TGX-221, therefore, has considerable potential as a novel chemotherapy agent for prostate cancer, its poor solubility and lack of selectivity for prostate cancer cells limit its clinical application. We have recently synthesized a TGX- 221 derivative, TGX-D1, which contains a hydroxyl group for peptide conjugation but exhibits similar activity and isoform-specificity as TGX-221. In this project, we will replace the –OH of TGX-D1 with –SH to form TGX-SH, which will have better stability in the serum. The overall objectives of this project are: 1) to develop a novel peptide-modified TGX-SH to overcome the two potential obstacles of TGX-221, poor solubility and lack of specificity to prostate cancer cells; 2) to evaluate its therapeutic effectiveness in combination with other anti-prostate cancer agents. The long-term goal of this project is to develop a peptide-based platform that may be used for not only TGX-SH but also other anti-prostate cancer agents that face poor solubility and poor tissue- specificity. Approximately 40% of new chemical entities in drug discovery are lipophilic and fail to reach market due to poor solubility. Not to mention that lack of tissue specificity is another major challenge for most chemical entities. Successful completion of the proposed studies may provide a promising concept for other small molecule drugs that face similar clinical challenges, poor stability and lack of target-ability.