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

• 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
• 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

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.

尽管引入了新的抗肿瘤骨髓瘤（MM）治疗方案，例如硼替佐米（硼替佐米（前十大最佳） 销售癌症药物），高MM继电器率和耐药性以及有问题的神经病和 血小板减少症的副作用继续困扰当前的疗法。此外，〜30％MM患者从未 应对硼替佐米治疗。特别是，由 高副蛋白血症和高钙血症一直是严重的后遗症，与之密不可分地联系在一起 MM肿瘤进展。到目前为止，MM疾病仍然是美国第二常见的血液系统恶性肿瘤 并且中位生存期3至5年无法治愈。那是新型的MM药物靶标和新的小分子问题 迫切需要了解与疾病相关的途径并促进抗MM药物发现。 这项快速提案寻求支持加速FDA的临床前评估 开发了高效率/低毒性小分子，靶向蛋白质p62（Secestosome 1，SQSTM1），因此 称为p62zz抑制剂。 p62zz抑制剂作为一种新型抗MM药物治疗的科学基础包括：i） 第一个p62-zz拮抗剂小分子的创新发现，表现出对人MM的显着抑制 如我们最近的出版物和专利所报道的细胞生长； ii）p62-target的固体实验确认 特异性，表明骨髓基质细胞中p62的下调或缺失显着降低 PKCζ，VCAM-1，TNF-α和IL-6的表达水平，还改善了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结构域是特异性的 通过非典型PKC，NF-κB，MAPK和IL-6产生的MM细胞生长和破骨细胞激活的细胞支持； iv） 发现的p62-zz小分子抑制剂显示出有希望的药物PK/PD生物利用度和低 与对照组相比，毒性特征可以显着抑制MM肿瘤的生长（> 75％） 人类MM Xenographic鼠模型； v）p62-zz小分子诱导戏剧性的新骨形成 在免疫能力的小鼠模型中有选择地在含MM的骨骼中。那是NIH快速轨道的目标是 进行促进的临床前研究和发展工作，以推动发现/报道的小型 - 分子药物候选者进入下一阶段，以进行规模化的化学合成和辅助 毒理学和有效研究。将候选毒品候选人带入定义的里程碑将快速进行 通过与大型制药/生物技术公司的共同开发合作伙伴关系以及 显着增加了吸引额外私人金融投资的机会，最终导致了多个 骨髓瘤药物临床试验。