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: 9383987
• 负责人: Kun Cheng
• 金额: $ 31.15万
• 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 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9383987
• 关键词: American; Androgens; Bacteriophages; Biodistribution; Blood; Blood Circulation; Cause of Death; Cells; Chemicals; Cleaved cell; Clinical; Clinical Research; Data; Development; Diagnosis; Dimerization; Dipeptides; Disulfides; ERBB2 gene; Early Diagnosis; Effectiveness; Endocytosis; Enzymes; Esters; Exhibits; FOLH1 gene; Face; Future; Goals; Growth; Hormone Responsive; In Vitro; Inbred BALB C Mice; LNCaP; Ligands; Link; Malignant Neoplasms; Malignant neoplasm of prostate; Modification; Neoplasm Metastasis; Operative Surgical Procedures; Oxidation-Reduction; Pathway interactions; Peptides; Pharmaceutical Preparations; Pharmacology; Phosphatidylinositols; Phosphotransferases; Prostatic Neoplasms; Protein Isoforms; Research; Serum; Signal Pathway; Site; Solubility; Specificity; Technology; Therapeutic Agents; Tissues; Toxicology; Treatment Efficacy; Use Effectiveness; Water; base; cancer therapy; castration resistant prostate cancer; chemotherapy; clinical application; combinatorial; dimer; disulfide bond; drug discovery; expectation; hydroxyl group; improved; in vivo; innovation; interstitial; kinase inhibitor; lipophilicity; male; men; mouse model; neoplastic cell; novel; overexpression; peptide drug; preclinical study; premature; prostate cancer cell; prostate cancer model; protein aminoacid sequence; small molecule; small molecule inhibitor; targeted delivery; therapeutic effectiveness; tumor; tumorigenesis; uptake

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.

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， 许多PI 3 K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，亚型PI 3 K-p100 β是 对于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 新型、亚型特异性、强效的PI 3 K-p100 β小分子抑制剂。而TGX-221， 因此，作为前列腺癌的新型化疗药物具有相当大的潜力， 溶解性和对前列腺癌细胞缺乏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，它含有一个羟基， 肽缀合，但表现出与TGX-221相似的活性和同种型特异性。在这 项目，我们将用-SH取代TGX-D1的-OH，形成TGX-SH，这将具有更好的 血清中的稳定性。 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）评估其与其他药物组合的治疗效果 抗前列腺癌剂。该项目的长期目标是开发一种基于肽的 该平台不仅可用于TGX-SH，还可用于其他抗前列腺癌药物， 溶解性差和组织特异性差。 在药物发现中，大约40%的新化学实体是亲脂性的， 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的 对大多数化学物质的挑战。成功完成拟议的研究可以提供 对于其他面临类似临床挑战的小分子药物来说， 稳定性和缺乏针对性。