Novel Inhibitors of Multi-Drug-Resistant Mutants of BCR-ABL for the Treatment of Chronic Myelogenous Leukemia (CML) and Ph Positive Acute Lymphocytic Leukemia (ALL).

 描述(由申请人提供)：这是一项第一阶段的SBIR申请，题为“用于治疗慢性粒细胞白血病(CML)和Ph+急性淋巴细胞白血病(ALL)的bcr-abl多药耐药突变的新型抑制剂。”这项提案的总体目标是进一步优化和提高HPRL利用白血病小鼠模型发现、开发和申请专利的新型化合物的疗效。第二个目标是进一步优化两到三个细胞特异性和卵子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)和Ph+急性淋巴细胞白血病(ALL)的发展中至关重要的癌蛋白。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，以进一步开发和商业化最初在Charles Sawyers博士的实验室取得的发现，当时他的实验室位于加利福尼亚州洛杉矶的加州大学洛杉矶分校(UCLA)。这些发现已经由加州大学洛杉矶分校独家授权给HPRL用于治疗应用。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HPRL顾问、现供职于加州大学旧金山分校(UCSF)的Neil Shah博士，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，并被世界上大多数最好的基于研究的制药公司使用。在这个领域， 诺华和Ariad都已经从HPRL获得了某些与BCR-ABL相关的知识产权的再许可，独立地验证了该技术的水平。其他许可证预计将在不久的将来发放。百时美施贵宝公司负责肿瘤学、研究和评估的副总裁拉加布博士和诺华公司董事会成员索耶斯博士发出的强烈支持信强调了人们对该项目的总体热情，并强调了成功满足这一迫切的未得到满足的医疗需求的重要性。

 DESCRIPTION (provided by applicant): This is a Phase I SBIR Application entitled "Novel Inhibitors of Multi-Drug-Resistant Mutants of BCR- ABL for the Treatment of Chronic Myelogenous Leukemia (CML) and Ph+ Acute Lymphocytic Leukemia (ALL)." The overall goal of this proposal is to further optimize and improve the efficacy of novel classes of compounds discovered, developed and patented by HPRL, using a mouse model of leukemia. A secondary goal is to further optimize two or three of the best lead candidates for cellular specificity and oal 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 development of chronic myelogenous leukemia (CML) and Ph+ Acute Lymphoblastic Leukemia (ALL). 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at Housey Pharmaceutical Research Laboratories (hereinafter "HPRL") to further develop and commercialize discoveries originally made in the laboratories of Dr.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., when his laboratory was located at the University of California at Los Angeles (UCLA), Los Angeles, CA. These discoveries have been exclusively licensed by UCLA 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., also an HPRL consultant and now at University of California at San Francisco (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 being utilized by the majority of the world's best research-based pharmaceutical concerns. In this field, both Novartis and Ariad have already sublicensed certain BCR-ABL-related Intellectual Property from HPRL, independently validating the caliber of the technology. Other licenses are anticipated in the near future. Strong Letters of support from Dr. Ragab, Vice President of Oncology, Search and Evaluation at Bristol Myers Squibb as well as Dr. Sawyers, who is also a Member of the Board of Directors at Novartis, highlight the overall enthusiasm for this project and underscore the importance of successfully addressing this urgent unmet medical need.