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。该提案旨在对一类新型磷脂酰肌醇3-激酶抑制剂进行临床前评价，以最终用作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)ProIX Pharmaceuticals已经鉴定出几种新型的绿青霉素类似物，它们对PI-3 K具有强效抑制作用，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)这些绿吡啶类似物对免疫缺陷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，并增强目前使用的细胞毒性和分子靶向（EGFR激酶）化疗药物的活性。从这组药剂中，ProIX选择了一种先导药物，并正在对这种药剂进行更广泛的临床前开发。由ProIX Pharmaceuticals进行的这项I期研究的目的是了解主导药物PX-866的生物活性。具体而言，其旨在1）确定PX-866在小鼠中的主要代谢物; 2）开发替代分子终点测定，并将这些终点与肿瘤中的靶向抑制相关联;以及3）确定PTEN在PX-866增强对EGFR激酶抑制剂的应答中的作用。该申请的结果将导致该药物更广泛的临床前开发，并将其推向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.