SQSTM1/p62-targeted Small Molecules for Multiple Myeloma Disease

SQSTM1/p62 靶向小分子治疗多发性骨髓瘤疾病

基本信息

批准号：
9347881
负责人：
James Lee
金额：
$ 30万
依托单位：
ID4PHARMA, LLC
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-23 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9347881
关键词：
Acceleration Adaptor Signaling Protein Adverse effects Agreement Antineoplastic Agents Binding Biological Assay Biological Availability Biotechnology Biotin Bone Diseases Bone Marrow Bortezomib Cell physiology Cells Chemicals Chemistry Clinical Data Clinical Trials Control Groups Development Disease Down-Regulation Drug Design Drug Kinetics Drug Targeting Drug resistance Exhibits FDA approved Funding GTF2H1 gene Genetic Goals Grant Growth Hematologic Neoplasms Human Hypercalcemia Immunocompetent In Vitro Inflammation Interleukin-6 Intervention Investigation Investigational Drugs Investigational New Drug Application Investments Kidney Failure Lead Legal patent Lesion Letters Licensing Link MAPK14 gene Manuscripts Marrow Measures Mitogen-Activated Protein Kinases Modification Multiple Myeloma Mus Nature Neurodegenerative Disorders Neuropathy Obesity Oral Osteoclasts Osteogenesis Osteolytic Ownership Oxis Pathway interactions Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmaceutical Technology Pharmacodynamics Pharmacology Pharmacotherapy Phase Physiologic pulse Plague Privatization Production Property Publications Quality Control Relapse Reporting Research Route Signal Pathway Signal Transduction Small Business Innovation Research Grant Solid Specificity Stromal Cells Supporting Cell Synthesis Chemistry TNF gene Technology Thrombocytopenia Time Toxic effect Toxicology Treatment Protocols United States National Institutes of Health Vascular Cell Adhesion Molecule-1 Work Xenograft procedure Zinc Fingers bone cell growth chemical property clinical investigation commercialization dosage drug candidate drug discovery experimental study improved in vivo inhibitor/antagonist innovation knockout gene leukemia mitogen-activated protein kinase p38 mouse model neurogenesis novel osteoclastogenesis pre-clinical pre-clinical research preclinical development preclinical evaluation preclinical study research and development scale up small molecule small molecule inhibitor tumor growth tumor progression tumorigenesis

项目摘要

Despite the introduction of new anti-multiple myeloma (MM) treatment regimens, such as Bortezomib (a top 10 best- selling cancer drug), high MM relapse rates and drug resistance as well as problematic neuropathy and thrombocytopenia side effects continue to plague the current therapies. Furthermore, ~30% MM patients never respond to Bortezomib treatment. Particularly, osteolytic bone diseases and renal failure resulting from hyperparaproteinemia and hypercalcemia have been the major serious sequelae that are inextricably linked with MM tumor progression. So far, MM disease remains the second most common hematological malignancy in the U.S. and incurable with a median survival of 3 to 5 years. Thus, novel MM drug targets and new small-molecule probes are in critical need both to understand the disease-associated pathways and to facilitate anti-MM drug discovery. This Fast Track proposal seeks support for acceleration of FDA IND-enabling preclinical evaluations of the developed high-efficacy/low-toxicity small-molecules, targeting the protein p62 (sequestosome 1, SQSTM1), so called p62ZZ inhibitors. The scientific basis for p62ZZ inhibitors as a novel anti-MM pharmacotherapy includes: i) the innovative discovery of first p62-ZZ antagonist small-molecules, exhibiting significant inhibition of human MM cell growth as reported in our recent publications and patents; ii) the solid experimental confirmation of p62-target specificity, revealing that down regulation or deletion of p62 in marrow stromal cells significantly decreased expression levels of PKCζ, VCAM-1, TNF-α and IL-6, and also decreased the stromal cell support of MM cell growth; iii) the strong experimental verification, showing that ZZ domain of p62 is specifically required for stromal cell support of MM cell growth and osteoclast activation through atypical PKC, NF-κB, MAPK and IL-6 production; iv) the discovered p62-ZZ small-molecule inhibitors demonstrated promising drug PK/PD bioavailability and low toxicity profiles, and can significantly inhibit MM tumor growth (>75%) compared with the control group in in vivo human MM xenograft murine model; and v) p62-ZZ small-molecules induce dramatic new bone formation selectively in MM-containing bones in an immunocompetent mouse model. Thus, the goal of the NIH Fast Track is to carry out IND-enabling preclinical research and development work to advance the discovered/reported small- molecule drug candidates to the next stage for undertaking scale-up chemistry synthesis and IND-enabling toxicology and efficacy investigations. Bringing drug candidates to the defined milestones will fast-track commercialization opportunities via co-development partnerships with major pharma/biotech companies and also significantly enhance the chances of attracting additional private financial investments, leading ultimately to multiple myeloma disease drug clinical trials.

尽管引入了新的抗多发性骨髓瘤 (MM) 治疗方案，例如硼替佐米（排名前 10 位的最佳治疗方案）销售抗癌药物）、高 MM 复发率和耐药性以及有问题的神经病变和此外，约 30% 的 MM 患者从未出现过血小板减少症副作用。对硼替佐米治疗有反应，特别是溶骨性骨病和肾功能衰竭。高副蛋白血症和高钙血症是与疾病密切相关的主要严重后遗症。迄今为止，MM 疾病仍然是美国第二常见的血液恶性肿瘤。且无法治愈，中位生存期为 3 至 5 年，因此需要新的 MM 药物靶点和新的小分子探针。迫切需要了解疾病相关途径并促进抗 MM 药物的发现。该快速通道提案寻求支持加速 FDA IND 支持的临床前评估开发了高效/低毒的小分子，靶向蛋白p62（sequestosome 1，SQSTM1），因此 p62ZZ 抑制剂作为新型抗 MM 药物疗法的科学依据包括： i) 首个p62-ZZ拮抗剂小分子的创新发现，对人类MM具有显着抑制作用我们最近的出版物和专利中报道的细胞生长；ii) p62-靶标的可靠实验证实特异性，揭示骨髓基质细胞中 p62 的下调或缺失显着减少 PKCδ、VCAM-1、TNF-α 和 IL-6 的表达水平，并且还降低了 MM 细胞的基质细胞支持生长；iii) 强有力的实验验证，表明 p62 的 ZZ 结构域是基质特别需要的通过非典型 PKC、NF-κB、MAPK 和 IL-6 产生支持 MM 细胞生长和破骨细胞激活；iv) 发现的 p62-ZZ 小分子抑制剂表现出有前途的药物 PK/PD 生物利用度和低毒性特征，与体内对照组相比，可显着抑制 MM 肿瘤生长（>75%）人类 MM 异种移植小鼠模型；和 v) p62-ZZ 小分子诱导显着的新骨形成因此，NIH 快速通道的目标是在免疫功能正常的小鼠模型中选择性地检测含有 MM 的骨骼。开展支持 IND 的临床前研究和开发工作，以推进发现/报告的小分子候选药物进入下一阶段进行放大化学合成和 IND 支持毒理学和功效研究将加快候选药物达到既定里程碑的速度。通过与主要制药/生物技术公司共同开发合作伙伴关系获得商业化机会显着提高吸引更多私人金融投资的机会，最终导致多重骨髓瘤疾病药物临床试验。