IGF::OT::IGF: SBIR Phase II, Topic 326: Development of Novel Therapeutic Agents that Target Cancer

IGF::OT::IGF：SBIR II 期，主题 326：针对癌症的新型治疗药物的开发

• 批准号: 9569000
• 负责人: Rajappa Kenchappa
• 金额: $ 147.5万
• 依托单位: TRANSGENEX NANOBIOTECH, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9569000
• 关键词: Biological Assay; Clinical; Computer Simulation; Contracts; Development; Documentation; Drug Kinetics; Generations; Lead; Malignant Neoplasms; Malignant neoplasm of lung; Mus; Pharmacodynamics; Phase; Relapse; Role; Scientist; Small Business Innovation Research Grant; Stem cells; Toxic effect; Validation; acute toxicity; atrial natriuretic factor receptor A; inhibitor/antagonist; novel therapeutics; phase 2 study; research and development; small molecule libraries; targeted treatment; tumor; tumor progression

Over the past decade, it has become abundantly clear that cancer-initiating stem cell (CSC) elimination is imperative to ‘cure’ cancer. Unfortunately, most of the existing clinical therapies target the bulk tumor and spare the very small number CSCs comprising <~1% of tumor, which expand after completion of therapy and cause relapse. Transgenex Nanobiotech Inc. (TGN) R & D has demonstrated the feasibility of targeting natriuretic peptide receptor A (NPRA) to cease tumor progression, however NPRA’s role in CSCs was unclear. In the phase I contract, TGN scientists developed a library of small molecules by computer modelling and screened them for their capacity to target CSC. This led to identification and validation of compound #2, heretofore designated NRI20152, as a bona-fide inhibitor of NPRA. NRI20152 showed anti-CSC activity in 3 generations of sphere-forming assays and it showed no harmful effect in mice in the pilot acute toxicity studies.

在过去的十年中，已经非常清楚的是，癌症起始干细胞（CSC）消除对于“治愈”癌症至关重要。 不幸的是，大多数现有的临床疗法靶向大块肿瘤，而不包括占肿瘤<~1%的非常少量的CSC，这些CSC在治疗完成后扩张并导致复发。 Transgenex Nanobiotech Inc (TGN)研发已经证明了靶向利尿钠肽受体A（NPRA）以阻止肿瘤进展的可行性，然而NPRA在CSC中的作用尚不清楚。在第一阶段合同中，TGN科学家通过计算机建模开发了一个小分子库，并筛选了它们靶向CSC的能力。这导致鉴定和验证化合物#2，迄今为止命名为NRI 20152，作为真正的NPRA抑制剂。 NRI 20152在3代成球试验中显示出抗CSC活性，在初步急性毒性研究中对小鼠无有害作用。