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，如硼替佐米（前10名最佳治疗方案）， 销售癌症药物），高MM复发率和耐药性以及有问题的神经病变， 血小板减少症的副作用继续困扰着目前的治疗。此外，约30%的MM患者从未 对硼替佐米治疗有反应特别是，溶骨性骨疾病和肾衰竭导致的 高副蛋白血症和高钙血症一直是主要的严重后遗症， 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恶性肿瘤。 并且无法治愈，中位生存期为3至5年。因此，新型MM药物靶标和新型小分子探针 对于了解疾病相关途径和促进抗MM药物的发现都是迫切需要的。 本快速通道提案寻求对加速FDA IND支持的临床前评价的支持， 开发了高效/低毒的小分子，靶向蛋白质p62（隔离体1，SQSTM 1）， p62 ZZ抑制剂p62 ZZ抑制剂作为新型抗MM药物疗法的科学基础包括：i） 首次创新性发现p62-ZZ拮抗剂小分子，对人MM表现出显著抑制作用 如我们最近的出版物和专利中所报道的细胞生长; ii）p62靶点的可靠实验证实 特异性，揭示骨髓基质细胞中p62的下调或缺失显著降低 MMP-1、VCAM-1、TNF-α和IL-6的表达水平降低，基质细胞支持减少 iii）强有力的实验验证，表明p62的ZZ结构域是基质细胞生长所特异性需要的。 通过非典型PKC、NF-κB、MAPK和IL-6产生对MM细胞生长和破骨细胞活化的细胞支持; iv） 所发现的p62-ZZ小分子抑制剂显示出有前景的药物PK/PD生物利用度和低 毒性特征，并且与对照组相比，在体内可以显著抑制MM肿瘤生长（>75%） 人MM异种移植鼠模型;和v）p62-ZZ小分子诱导显著新骨形成 选择性地在免疫活性小鼠模型中的含MM的骨中。因此，NIH Fast Track的目标是 开展IND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，进行规模化化学合成和IND使能 毒理学和功效研究。使候选药物达到规定的里程碑将加快 通过与主要制药/生物技术公司的共同开发伙伴关系获得商业化机会， 大大增加吸引更多私人金融投资的机会，最终导致多个 骨髓瘤疾病药物临床试验。