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

摘要 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各种临床前和临床研究 癌症疗法。我们和其他人已经证明了异构体PI3K-P100β对于 前列腺癌的肿瘤发生和雄激素非依赖性进展。TGX-221是一种新颖的异构体- PI3K-P100β的特异性和强效小分子抑制剂。而TGX-221因此具有 作为一种新型的前列腺癌化疗药物，它具有相当大的潜力，但其溶解性差，缺乏 对前列腺癌细胞的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，它含有用于肽连接的羟基，但表现出类似的 活性和异构体专一性与TGX-221一致。在本项目中，我们将TGX-D1中的-OH替换为-SH 形成TGX-SH，在血清中具有较好的稳定性。 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：溶解性差和对前列腺缺乏特异性 2)评价其与其他抗前列腺癌药物的联合治疗效果。 探员们。这个项目的长期目标是开发一个基于多肽的平台，可以用于 不仅是TGX-SH，还有其他面临溶解性和组织不良的抗前列腺癌药物- 专一性。 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 大多数化学物质。成功完成拟议的研究可能会提供一个有希望的 其他小分子药物面临类似临床挑战、稳定性差和缺乏 目标能力。

Abstract 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.