PI-3 kinase inhibitor PX-866 as anticancer therapy

描述（由申请人提供）：在美国，每四个人中就有一个死于癌症。在美国，整个抗癌药物市场超过20亿美元。有必要确定新的和选择性的基于小分子的癌症治疗方法。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，以最终使用该药物PX-866作为治疗实体癌和血液病的药物。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）通路是在多种人类癌症中被激活的生存信号通路。2) PTEN是一种脂质磷酸酶，通过去磷酸化pi -3-磷酸盐来减弱PI-3K信号，在大量人类肿瘤中缺失，导致PI-3K/Akt生存信号通路组成性激活。3) ProlX制药公司已经发现了几种新型的viridin类似物，它们显示出对PI-3K的有效抑制，具有更好的生物稳定性，并且没有wortmannin的严重肝毒性。4)其中一种viridin类似物对免疫缺陷小鼠的多种人类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已选择PX-866作为PI-3K抑制剂的先导，作为一种新的癌症治疗药物。该2期申请将由ProlX制药公司进行，目的是通过完成探索性IND，进一步推进PX-866的临床试验，从而实现安全性、配方和生物学终点研究。具体而言，其目的是1)开发静脉注射和口服PX-866制剂，并进行相应的稳定性研究；2)比较和启动替代分子终点测定的验证；3)评估PX-866在大鼠和狗身上的安全性，为随后的0期临床试验确定剂量。该申请的结果将导致提交探索性IND申请，允许该药物通过新制定的临床药代动力学研究指南在临床中进行评估。ProlX拥有独家开发抗癌药物PX-866制剂的许可。

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.