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 血小板减少症的副作用继续困扰着当前的治疗方法。此外，约 30% MM 患者从未 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。 MM 肿瘤进展。到目前为止，多发性骨髓瘤仍然是美国第二大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，新的多发性骨髓瘤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 称为 p62ZZ 抑制剂。 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 的产生，为 MM 细胞生长和破骨细胞激活提供细胞支持；四） 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； v) p62-ZZ 小分子诱导显着的新骨形成 选择性地存在于免疫活性小鼠模型中含有 MM 的骨骼中。因此，NIH 快速通道的目标是 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。使候选药物达到既定的里程碑将加快进程 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。