Move FL118 anticancer drug or its analogs into the clinic to benefit patients: Task 1 – i.v. Efficacy and PK studies (FL118 系列抗癌新药的临床前研发和临床推广)
The anticancer drug FL118 together with its potential analogs is on the top priority to be developed in Canget Company (www.canget-biotek.com). We are planning to move FL118 in parallel with its possible analogs toward clinical trials and finally reaching our goal of marketing these novel drugs in clinical practice for benefiting cancer patients. FL118 was demonstrated to be able to eliminate both small and large human tumors in animal models without relapse.
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We recently described a novel small chemical molecule (designated FL118) with unusual anticancer activity (http://www.fiercebiotechresearch.com/story/roswell-park-researchers-spot-versatile-cancer-treatment/2012-09-21). FL118 is able to inhibit a broad-spectrum of antiapoptotic gene products (Survivin, Mcl-1, XIAP, cIAP2), and is much superior to FDA-approved anticancer drugs (e.g. irinotecan, topotecan, doxorubicin, 5-FU, gemcitabine, docetaxel, oxaliplatin, cytoxan and cisplatin). We have preliminary data showing a promising therapeutic index (TI = 2-3), pharmacokinetics, efficacy, and safety profile of FL118 when delivered via an intraperitoneal (i.p.) route. Since i.p. is a rare route in the clinic, we have developed a new recipe that is clinically compatible to the intravenous (i.v.) route to deliver FL118. To this end, we will determine the TI of FL118 via i.v. and evaluate terminal half-life of FL118 in blood plasma, various organs and tumor tissues. We will then carry out necessary PK (Pharmacokinetics), ADME (Absorption Distribution Metabolism Excretion)/Tox (Toxicology), and efficacy studies, CMC (Chemistry, Manufacturing and Controls) and cGMP (Current Good Manufacturing Practice) studies. Then, we will file an IND at the FDA to move FL118 into clinical trials to benefit cancer patients. Of an important note, we also identified several promising backup small chemical compounds, and have a medicinal chemistry program underway. This strategy would significantly decrease the risk for reaching our final goal to move promising anticancer drugs for cancer treatment in clinical practice. 近来，我们发现了一种具有非凡抗癌特性的新奇小分子（命名为FL118, www.bioon.com/tm/cancer/530162.shtml). FL118系列抗癌新药能抑制广谱的抗凋亡基因产物 (Survivin, Mcl-1, XIAP, cIAP2) 。在动物实验中表明，FL118比美国食品及药物管理局(FDA)批准的最常用抗癌药物优越的多（例如, 依立替康、拓扑替康、阿霉素、5-氟尿嘧啶、吉西他滨、多烯紫衫醇、奥沙利铂、环磷酰胺、顺铂）。 FL118的原始数据表明该药在通过腹腔注射进入动物体时，其治疗指数(TI) 大约为2-3、药物代谢动力学、药效、药物安全性都较优越。但是腹腔注射在临床上很少使用, 因此我们进一步开发了符合临床静脉注射输送的FL118制作配方。至此，我们必须确定 FL118 在这一新的静脉注射输送法中的治疗指数 (TI)，在血浆和各种组织及肿瘤中的半衰期。接下去，我们须进行必要的药物代谢动力学、毒理学及药效代谢研究，以及化学、制造控制和现行药品生产管理规范的研究。然后，向FDA申请FL118的新药临床试验，以早日造福癌症患者。 另外重要的一点是我们还初步确定了其他几种有前途的小分子类似物作为可能的替补药物。同时我们还有药物化学合成的合作研究项目在进行中。这种策略可以大大降低我们实现目标的风险，以加速推动优质抗癌药物用于癌症的临床治疗。
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- TYPE OF GRANT: Research Idea AwardRECEIVED BY TEAM MEMBER(S):DESCRIPTION: The goal of this project is to identify new drug targets using an extraordinary small antitumor molecule FL118 as bait/probe for studies of its mechanism of action in (prostate) cancer cells.ISSUING AGENCY: US Army Department of DefenseAMOUNT: $628DATE RECEIVED: 04/10/2013STATUS: InactivePATENT NAME: Compositions and Methods for Identifying Agents that Alter Expression of SurvivinPATENT NUMBER: US 7,569,221 B2Inventor's: Fengzhi LiDATE RECEIVED: 08/04/2009ASSIGNEE: Roswell Park Cancer InstitutePATENT NAME: Novel Formulations of Water-Insoluble Chemical Compounds and Methods of Using a Formulation of Compound FL118 for Cancer TherapyPATENT NUMBER: Non-provisional patent in pendingInventor's: Fengzhi Li, Xiang Ling and Shousong CaoDATE RECEIVED: 10/31/2011ASSIGNEE: Roswell Park Cancer Institute
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