PI-3 kinase inhibitor PX-866 as anticancer therapy

描述（由申请人提供）：美国每四例死亡中就有一例是由于癌症。在美国，整个癌症药物市场超过20亿美元。非常需要鉴定新的和选择性的基于小分子的癌症疗法。该提案旨在进行一种新型磷脂酰肌醇3-激酶抑制剂的后期临床前开发，以最终使用PX-866作为治疗实体瘤和血液癌的药物。有强有力的证据表明：1）磷脂酰肌醇-3-激酶（PI-3 K）/Akt（蛋白激酶B）途径是一种生存信号途径，在许多类型的人类癌症中被激活。2)PTEN是一种通过使PI-3-磷酸去磷酸化来减弱PI-3 K信号传导的脂质磷酸酶，其在大量人类肿瘤中丢失，导致PI-3 K/Akt存活信号传导途径的组成性激活。3)ProlX制药公司已经确定了几种新型的绿青霉素类似物，它们显示出对PI-3 K的有效抑制，具有更好的生物稳定性，并且没有渥曼青霉素的严重肝毒性。4)其中一种病毒素类似物对免疫缺陷SCID小鼠中的许多人肿瘤异种移植物显示出良好的单药抗肿瘤活性，并增强了目前使用的细胞毒性和分子靶向（EGFR激酶）化疗药物的活性。ProlX选择PX-866作为主要的PI-3 K抑制剂，以开发一种新型的癌症治疗方法。由ProlX Pharmaceuticals进行的这项2期申请的目的是通过完成探索性IND，使安全性，制剂和生物学终点研究进一步推进PX-866的临床试验。具体而言，其目的是：1）开发PX-866的静脉和经口制剂，并进行相应的稳定性研究; 2）比较并启动替代分子终点试验的验证; 3）评价PX-866在大鼠和犬种属中的安全性，以确定随后0期临床试验的剂量。该申请的结果将导致提交探索性IND申请，允许通过新制定的临床药代动力学研究指南在临床上对药物进行评价。ProlX拥有开发PX-866作为抗癌药物的独家许可。

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.