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).

BCR-ABL 多重耐药突变体的新型抑制剂，用于治疗慢性粒细胞白血病 (CML) 和 Ph 阳性急性淋巴细胞白血病 (ALL)。

• 批准号: 9047400
• 负责人: GERARD M HOUSEY
• 金额: $ 23.9万
• 依托单位: HOUSEY PHARMACEUTICAL RESEARCH LAB
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-24 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9047400
• 关键词: Acute Lymphocytic Leukemia; Address; Adverse effects; Area; Arrhythmia; Award; Biological Assay; Biological Availability; Caliber; California; Cancer Center; Cells; Chairperson; Chronic Myeloid Leukemia; Clinical; Coagulants; Dasatinib; Development; Disease; Doctor of Medicine; Drug resistance; Evaluation; Exhibits; Foundations; Future; Gleevec; Goals; Human; Imatinib; Imatinib mesylate; Intellectual Property; Investigational Drugs; Laboratories; Laboratory Research; Lead; Legal patent; Letters; Licensing; Life; Los Angeles; Marketing; Mediating; Medical; Medicine; Memorial Sloan-Kettering Cancer Center; Modeling; Molecular; Multi-Drug Resistance; Mus; Mutation; Myocardial Infarction; Oncogene Proteins; Oral; Pathogenesis; Patients; Ph+ ALL; Pharmacologic Substance; Phase; Phase I Clinical Trials; Philadelphia Chromosome Negative Chronic Myelogenous Leukemia; Phosphotransferases; Plague; Prize; Probability; Process; Protein Kinase; Pulmonary Embolism; Request for Proposals; Research; Resistance; Resistance development; Resources; San Francisco; Scientist; Seminal; Series; Small Business Innovation Research Grant; Solid; Specificity; Sprycel; Stroke; Technology; Testing; Therapeutic; Time; Toxic effect; United States; United States Food and Drug Administration; United States National Institutes of Health; Universities; Work; base; bcr-abl Fusion Proteins; clinically relevant; improved; inhibitor/antagonist; leukemia; member; mouse model; mutant; novel; oncology; pre-clinical; professor; programs; public health relevance; scaffold; tumor

 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.

 描述（由申请人提供）：这是一项 I 期 SBIR 申请，标题为“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 多重耐药突变体的新型抑制剂”。该提案的总体目标是使用小鼠模型进一步优化和提高由 HPRL 开发并获得专利的新型发现化合物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。与该提案相关的所有 HPRL 化合物都是 BCR-ABL 癌基因产物（一种癌蛋白）的 T315I 突变体的纳摩尔抑制剂。这对于慢性粒细胞白血病 (CML) 和 Ph+ 急性淋巴细胞白血病 (ALL) 的发展至关重要。 NIH 的支持将用于重点研究。在 Housey 药物研究实验室（以下简称“HPRL”）工作，负责开发最初在医学博士 Charles Sawyers 博士的实验室中取得的发现并将其商业化，当时他的实验室位于加利福尼亚州洛杉矶市的加州大学洛杉矶分校 (UCLA)这些发现已获得加州大学洛杉矶分校独家授权 HPRL 用于治疗应用。该第一阶段提案建立在索耶斯博士及其同事在加州大学洛杉矶分校期间建立的坚实科学基础之上。 Sawyers 博士和他的同事，包括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。 Neil Shah 医学博士，同时也是 HPRL 顾问，现就职于加州大学旧金山分校 (UCSF)，他围绕甲磺酸伊马替尼 (Gleevec) 耐药性的发展做出了开创性的发现，该药物已他们还为达沙替尼 (Sprycel) 的开发做出了重大贡献，这种化合物能够治疗部分但不是全部 CML 患者中出现的 BCR-ABL 突变。该提案为进一步开发和商业化最初由 NIH 支持的加州大学洛杉矶分校 (UCLA) 纪念斯隆管理学院的科学家们创造的关键知识产权和技术提供了独特的机会。凯特林癌症中心 (MSKCC) 和加州大学旧金山分校 (UCSF) 是该领域公认的领导者，该提案汇集了伊马替尼耐药领域领导者的学术专业知识与 Housey 药物研究实验室 (HPRL)。该组织的科学家在创造、开发和商业化具有巨大市场价值的知识产权和技术方面拥有良好的记录，最初由 Housey 科学家开发的细胞分析技术已获得许可，并被世界上大多数最优秀的研究机构所使用。基于在这个领域， 诺华和 Ariad 均已从 HPRL 获得了某些 BCR-ABL 相关知识产权的再许可，预计在不久的将来还会获得来自搜索肿瘤学副总裁 Ragab 博士的强烈支持信。百时美施贵宝 (Bristol Myers Squibb) 以及诺华 (Novartis) 董事会成员索耶斯 (Sawyers) 博士的评价和评估强调了对该项目的整体热情，并强调了成功的重要性解决这一紧迫的未满足的医疗需求。