PI-3 kinase inhibitor PX-866 as anticancer therapy

描述(申请人提供)：在美国，每四个人中就有一个死于癌症。美国的抗癌药物市场总额超过20亿美元。有必要确定新的和选择性的基于小分子的癌症疗法。这项提议寻求进行一种新的磷脂酰肌醇3-激酶抑制剂的晚期临床前开发，以最终将该试剂PX-866用作治疗实体和血液病癌症的药物。有强有力的证据表明：1)磷脂酰肌醇-3-激酶(PI-3K)/Akt(蛋白激酶B)通路是一种生存信号通路，在许多类型的人类癌症中都被激活。2)PTEN是一种通过去磷酸化PI-3-磷酸来减弱PI-3K信号转导的脂质磷酸酶，在许多人类肿瘤中缺失，导致PI-3K/Akt生存信号通路的结构性激活。3)ProlX制药公司已经确定了几个新的绿素类似物，它们对PI-3K具有较强的抑制作用，具有更好的生物稳定性，并且没有Wortmannin的严重肝脏毒性。4)其中一种绿素类似物对免疫缺陷的SCID小鼠移植瘤表现出良好的单药抗肿瘤活性，并增强了目前使用的细胞毒和分子靶向(EGFR)化疗药物的活性。ProlX已经选择PX-866作为主要的PI-3K抑制剂来开发一种新的癌症治疗方法。由ProlX制药公司进行的这一第二阶段应用的目标是通过完成能够实现安全性、配方和生物终点的探索性IND研究，进一步推动PX-866进入临床试验。具体地说，它的目的是1)开发PX-866的静脉和口服制剂，进行相应的稳定性研究；2)比较并启动替代分子终点分析的验证；以及3)评估PX-866在老鼠和狗身上的安全性，以确定随后进行的0期临床试验的剂量。这项申请的结果将导致提交一份探索性的IND申请，允许通过新开发的临床药代动力学研究指南在临床上对该药物进行评估。ProlX拥有开发PX-866抗癌药物的独家许可证。

DESCRIPTION (provided by applicant): One in every four deaths in the US is due to cancer. The overall cancer drug market exceeds $2 billion in the USA. There is significant need to identify novel and selective small molecule-based cancer therapies. This proposal seeks to undertake late preclinical development of a novel inhibitor of phosphatidyl inositol 3-kinase for the eventual use of the agent, PX-866, as a therapy against solid and hematologic cancers. There is strong evidence for the following: 1) The phosphatidylinositol-3-kinase (PI-3K)/Akt (protein kinase B) pathway is a survival signaling pathway that is activated in many types of human cancer. 2) PTEN, a lipid phosphatase that attenuates PI-3K signaling by dephosphorylating PI-3-phosphates, is lost in a large number of human tumors leading to constitutive activation of PI-3K/Akt survival signaling pathway. 3) ProlX Pharmaceuticals has identified several novel viridin analogues that show potent inhibition of PI-3K, with better biological stability and without the severe liver toxicity of wortmannin. 4) One of these viridin analogues shows good single agent antitumor activity against a number of human tumor xenografts in immunodeficient scid mice and potentiates the activity of both currently used cytotoxic and molecularly targeted (EGFR kinase) chemotherapeutic drugs. ProlX has selected PX-866 as the lead PI-3K inhibitor to develop as a novel cancer therapy. The objectives of this Phase 2 application to be conducted by ProlX Pharmaceuticals, are to further advance PX-866 toward a clinical trial by completing Exploratory IND enabling safety, formulation and biological endpoint studies. Specifically it is intended 1) to develop intravenous and oral formulations of PX-866 with corresponding stability studies; 2) to compare and initiate validation of surrogate molecular endpoint assays; and 3) to evaluate the safety of PX-866 in rat and dog species to identify a dose for an ensuing Phase 0 clinical trial. The results of this application will lead to the submission of an Exploratory IND application allowing the agent to be evaluated in the clinic through the newly developed guidelines for clinical pharmacokinetic studies. ProlX has the exclusive license to develop PX-866 agent as an anticancer drug.