Novel Inhibitors for the Treatment of Highly Drug-Resistant Chronic Myelogenous

描述(由申请人提供)：这是SBIR建议的第一阶段应用，标题为“用于治疗高度耐药的慢性髓细胞性白血病的新型抑制剂”。这项建议的总体目标是测试一类由HPRL发现和开发的新型小分子支架在白血病小鼠模型中的疗效。第二个目标是进一步优化两到三个细胞特异性和口服生物利用度最好的候选药物。所有与这一建议相关的HPRL化合物都是bcr-abl癌基因产物的T315I突变的纳米分子抑制剂，bcr-abl癌基因产物是一种在慢性粒细胞白血病(CML)的发生中起核心作用的癌蛋白。NIH的支持将用于豪西药物研究实验室(以下简称“HPRL”)的重点研究，以进一步开发最初由加州大学洛杉矶分校(UCLA)医学博士Charles Sawyers的实验室做出的发现，并将其商业化，这些发现已被HPRL独家授权用于治疗用途。这项第一阶段的提案建立在索耶斯博士和他的同事在加州大学洛杉矶分校时建立的坚实的科学基础之上。索耶斯博士现在是纪念斯隆-凯特琳癌症中心人类肿瘤学和病理学项目的主席，也是HPRL的首席科学顾问委员会成员和这一治疗项目的高级顾问。在过去的八年里，Sawyers博士和他的同事，包括医学博士Neil Shah(现供职于加州大学旧金山分校)，围绕甲磺酸伊马替尼(Gleevec)耐药性的产生取得了开创性的发现，格列卫是一种彻底改变了慢性粒细胞白血病(CML)治疗的药物。他们还对达沙替尼(Sprycel)的开发做出了关键贡献，这是一种能够治疗CML患者最终产生伊马替尼耐药性的bcr-abl突变的化合物。该提案为进一步开发和商业化关键知识产权和技术提供了独特的机会，这些关键知识产权和技术最初是由NIH支持的加州大学洛杉矶分校(UCLA)、纪念斯隆·凯特琳癌症中心(MSKCC)和加州大学旧金山分校(UCSF)的科学家创造的，他们都是该领域公认的领导者。这项提案将伊马替尼耐药性领域的领先者与休西药物研究实验室(HPRL)的学术专业知识结合在一起。HPRL是一个组织，其科学家在创造、开发和商业化具有巨大市场价值的知识产权和技术方面有着良好的记录。最初由Housey科学家开发的基于细胞的分析技术已经获得许可，并在世界上大多数最好的研究驱动的制药公司中使用。公共卫生相关性：开发新的治疗药物，用于治疗耐药的慢性粒细胞白血病和其他形式的癌症。

DESCRIPTION (provided by applicant): This is the Phase 1 application of an SBIR proposal entitled "Novel Inhibitors for the Treatment of Highly Drug Resistant Chronic Myelogenous Leukemia." The overall goal of this proposal is to test the efficacy of a class of novel small molecule scaffolds, which have been discovered and developed by HPRL, in a mouse model of leukemia. A secondary goal is to further optimize two or three of the best lead candidates for cellular specificity and oral bioavailability. All of the HPRL compounds relevant to this proposal are nanomolar inhibitors of the T315I mutant of the BCR-ABL oncogene product, an oncoprotein which is of central importance in the develompent of chronic myelogenous leukemia (CML). The NIH support will be used to focus research at Housey Pharmaceutical Research Laboratories (hereinafter "HPRL") to further develop and commercialize discoveries originally made in the laboratories of Dr. Charles Sawyers, M.D., at the University of California at Los Angeles (UCLA), Los Angeles, CA, which have been exclusively licensed to HPRL for therapeutic applications. This Phase I proposal builds upon the solid scientific foundation established by Dr. Sawyers and his colleagues while at UCLA. Dr. Sawyers is now the Chairman of the Human Oncology and Pathogenesis Program at Memorial Sloan Kettering Cancer Center and serves as HPRL's Principal Scientific Advisory Board member and Senior Consultant with respect to this therapeutic program. Over the past eight years Dr. Sawyers and his colleagues, including Dr. Neil Shah, M.D. (now at UCSF), have made seminal discoveries surrounding the development of resistance to imatinib mesylate (Gleevec), a medicine which has revolutionized the treatment of chronic myelogenous leukemia (CML). They have also made key contributions to the development of dasatinib (Sprycel), a compound which is capable of treating some, but not all, of the BCR-ABL mutations that emerge in CML patients who eventually develop imatinib resistance. The proposal provides the unique opportunity to further develop and commercialize key intellectual property and technology originally created by NIH-supported scientists at the University of California at Los Angeles (UCLA), the Memorial Sloan Kettering Cancer Center (MSKCC), and the University of California at San Francisco (UCSF) who are acknowledged leaders in the field. The proposal brings together the academic expertise of leaders in the field of imatinib resistance with Housey Pharmaceutical Research Laboratories (HPRL), an organization whose scientists have a strong track record of creating, developing and commercializing intellectual property and technology of formidable market value. Cell-based assay technology originally developed by Housey scientists has been licensed and is in use at the majority of the world's best research-driven pharmaceutical concerns. PUBLIC HEALTH RELEVANCE: Development of novel therapeutic agents for the treatment of drug-resistant chronic myelogenous leukemia and other forms of cancer.