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

用于治疗晚期前列腺癌的水不溶性药物的肽缀合物

• 批准号: 10176872
• 负责人: Kun Cheng
• 金额: $ 3.08万
• 依托单位: UNIVERSITY OF MISSOURI KANSAS CITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10176872
• 关键词: American; Androgens; Cause of Death; Chemicals; Clinical; Clinical Research; Data; Diagnosis; Early Diagnosis; Exhibits; Face; Goals; Malignant Neoplasms; Malignant neoplasm of prostate; Modification; Neoplasm Metastasis; Operative Surgical Procedures; Pathway interactions; Peptides; Pharmaceutical Preparations; Phosphatidylinositols; Phosphotransferases; Protein Isoforms; Research; Serum; Signal Pathway; Solubility; Specificity; Tissues; Treatment Efficacy; Water; advanced prostate cancer; base; cancer therapy; chemotherapy; clinical application; drug discovery; expectation; hydroxyl group; innovation; kinase inhibitor; lipophilicity; male; men; novel; preclinical study; prostate cancer cell; small molecule; small molecule inhibitor; therapeutic effectiveness; tumorigenesis

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.

抽象的 磷酸肌醇3-激酶（PI3KS）信号通路是最重要的途径之一 癌症和许多PI3K抑制剂目前正在临床前和临床研究中 癌症疗法。我们和其他人已经证明了同工型PI3K-P100β对于 前列腺癌中的肿瘤发生和雄激素非依赖性进展。 TGX-221是一种小说，同工型 - PI3K-P100β的特异性和潜在的小分子抑制剂。因此，TGX-221具有 作为前列腺癌的新型化学疗法剂，其溶解度差和缺乏 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TGX- 221衍生物TGX-D1，其中含有用于肽结合的羟基，但表现出相似的 活性和同工型特异性作为TGX-221。在这个项目中，我们将用–sh替换TGX-D1的–OH 形成TGX-SH，在血清中将具有更好的稳定性。 该项目的总体目标是：1）开发一种新型的肽修饰的TGX-SH 克服TGX-221的两个潜在障碍，溶解度差和缺乏对前列腺的特异性 癌细胞； 2）评估其治疗效果与其他抗疾病癌的结合 代理商。该项目的长期目标是开发一个基于肽的平台，可用于 不一 特异性。 大约40％的药物发现新化学实体是亲脂性的，无法达到 市场由于溶解度差而引起的市场。更不用说缺乏组织特异性是另一个主要挑战 大多数化学实体。成功完成拟议的研究可能会提供诺言 其他小分子药物的概念，这些药物面临类似临床挑战，稳定性差和缺乏的概念 目标性。