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

摘要 磷脂酰肌醇3-激酶（PI 3 Ks）信号通路是细胞凋亡的重要信号通路之一， 目前，许多PI 3 K抑制剂正处于临床前和临床研究中， 癌症治疗我们和其他人已经证明，亚型PI 3 K-p100 β是必需的， 前列腺癌的肿瘤发生和雄激素非依赖性进展。TGX-221是一种新的同种型， PI 3 K-p100 β特异性且有效的小分子抑制剂。虽然TGX-221，因此， 作为前列腺癌的新型化疗剂具有相当大的潜力，其溶解性差且缺乏 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，其含有用于肽缀合的羟基，但表现出类似的 活性和异构体特异性与TGX-221相同。在本项目中，我们将用-SH替换TGX-D1的-OH 形成TGX-SH，其在血清中具有更好的稳定性。 本课题的总体目标是：1）开发一种新型肽修饰的TGX-SH， 克服了TGX-221溶解性差和对前列腺缺乏特异性这两个潜在障碍， 癌细胞; 2）评估其与其他抗前列腺癌药物联合的治疗效果 剂.该项目的长期目标是开发一种基于肽的平台，可用于 不仅是TGX-SH，而且还有其他抗前列腺癌药物，这些药物面临溶解性差和组织差的问题， 的特异性 在药物发现中，大约40%的新化学实体是亲脂性的， 市场上因溶解性差。更不用说缺乏组织特异性是另一个主要挑战， 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的临床挑战，稳定性差，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.