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

用于治疗高度耐药的慢性粒细胞性白血病的新型抑制剂

• 批准号: 7672146
• 负责人: GERARD M HOUSEY
• 金额: $ 14.96万
• 依托单位: HOUSEY PHARMACEUTICAL RESEARCH LAB
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-07 至 2010-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7672146
• 关键词: ADME Study; Animals; Biological Assay; Biological Availability; California; Cancer Center; Cells; Chairperson; Chronic; Chronic Myeloid Leukemia; Clinical; Dasatinib; Development; Disease; Doctor of Medicine; Drug Kinetics; Drug resistance; Exhibits; Foundations; Gleevec; Goals; Human; Imatinib; Imatinib mesylate; Intellectual Property; Investigational New Drug Application; Laboratories; Laboratory Research; Lead; Licensing; Liver Microsomes; Los Angeles; Malignant Neoplasms; Marketing; Mediating; Medicine; Memorial Sloan-Kettering Cancer Center; Modeling; Mus; Mutation; Myelogenous; Oncogene Proteins; Oral; Pathogenesis; Patients; Pharmacologic Substance; Phase; Phase I Clinical Trials; Phosphotransferases; Protein Kinase; Research; Resistance; Resistance development; Resources; San Francisco; Scientist; Seminal; Small Business Innovation Research Grant; Solid; Specificity; Sprycel; Technology; Therapeutic; Therapeutic Agents; Toxicology; United States National Institutes of Health; Universities; analog; anticancer research; base; bcr-abl Fusion Proteins; clinically relevant; efficacy testing; in vivo; inhibitor/antagonist; leukemia; member; mouse model; mutant; novel; novel therapeutics; oncology; pre-clinical; programs; public health relevance; scaffold; small molecule

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.

描述（由申请人提供）：这是SBIR提案的1期申请，标题为“治疗高度耐药慢性髓性白血病的新型抑制剂”。“该提案的总体目标是在白血病小鼠模型中测试HPRL发现和开发的一类新型小分子支架的功效。第二个目标是进一步优化细胞特异性和口服生物利用度的两个或三个最佳先导候选物。所有与该建议相关的HPRL化合物都是BCR-ABL癌基因产物的T315 I突变体的纳摩尔抑制剂，BCR-ABL癌基因产物是一种在慢性髓细胞性白血病（CML）的发展中至关重要的癌蛋白。 NIH的支持将用于Housey Pharmaceutical Research Laboratories（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，M.D.，在加州大学洛杉矶分校（UCLA），洛杉矶，CA，其已被HPRL独家许可用于治疗应用。 这个第一阶段的提案建立在Sawyers博士和他的同事在加州大学洛杉矶分校建立的坚实的科学基础之上。Sawyers博士现在是纪念斯隆-凯特琳癌症中心人类肿瘤学和发病机制项目的主席，并担任HPRL的首席科学顾问委员会成员和该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Neil Shah博士，医学博士，(now在加州大学旧金山分校），已经取得了开创性的发现，围绕耐药性的发展，伊马替尼甲磺酸盐（格列卫），一种药物，彻底改变了治疗慢性粒细胞白血病（CML）。他们还为达沙替尼（Sprycel）的开发做出了关键贡献，这种化合物能够治疗一些但不是全部的BCR-ABL突变，这些突变出现在最终发展为伊马替尼耐药的CML患者中。 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，这些知识产权和技术最初由美国国立卫生研究院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）和加州大学弗朗西斯科分校（UCSF）的科学家创建，他们是该领域公认的领导者。该提案汇集了伊马替尼耐药性领域领导者的学术专长与Housey制药研究实验室（HPRL），该组织的科学家在创造，开发和商业化具有强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检测技术已获得许可，并在世界上大多数最好的研究驱动的制药企业中使用。公共卫生相关性：耐药慢性粒细胞白血病和其他癌症的新型治疗药物的开发。