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。本提案旨在对一类新的磷脂酰肌醇3-激酶抑制剂进行临床前评估，以最终用于治疗实体癌和血液癌。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) ProIX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)这些绿蛋白类似物对免疫缺陷小鼠的许多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。ProIX已经从这组药物中选择了一种先导药物，并正在对该药物进行更广泛的临床前开发。ProIX制药公司进行的这项I期研究的目的是了解先导剂PX-866的生物活性。具体来说，它的目的是1)测定小鼠体内PX-866的主要代谢物；2)开发替代分子终点分析，并将这些终点与肿瘤中的靶点抑制联系起来；3)确定PTEN在增强PX-866对EGFR激酶抑制剂的反应中的作用。此次申请的结果将导致该药物更广泛的临床前开发，将其推向IND申请和I期临床试验。ProIX拥有开发这些药物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 preclinical evaluation of a novel class of inhibitors of phosphatidyl inositol 3-kinase for the eventual use of an agent 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) ProIX 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) These viridin analogues show good single agent antitumor activity against a number of human tumor xenografts in immunodeficient scid mice and potentiate the activity of both currently used cytotoxic and molecularly targeted (EGFR kinase) chemotherapeutic drugs. From this group of agents, ProIX has selected a drug lead and is undertaking more extensive pre-clinical development of this agent. The objectives of this Phase I study to be conducted by ProIX Pharmaceuticals are to gain an understanding of the biological activity of the lead agent, PX-866. Specifically it is intended 1) to determine major metabolites of PX-866 in mice; 2) to develop surrogate molecular endpoint assays, and relate these endpoints to target inhibition in tumors; and 3) to define the role of PTEN in the potentiation of the response to EGFR kinase inhibitors by PX-866. The results of this application will lead to more extensive pre-clinical development of the agent, progressing it toward an IND application and a Phase I clinical trial. ProIX has the exclusive license to develop these agents as an anticancer drug.