Ca2+/CaM-Dependent Protein Kinase II: A Novel Target in Osteosarcoma

Ca2 /CaM 依赖性蛋白激酶 II：骨肉瘤的新靶点

• 批准号: 8251055
• 负责人: Howard Schulman
• 金额: $ 27.92万
• 依托单位: ALLOSTEROS THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-14 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8251055
• 关键词: Adolescent; Allosteric Site; Animals; Apoptosis; Binding; Biochemical; Biological Assay; Biological Markers; Blood Vessels; Calcium/calmodulin-dependent protein kinase; Catalytic Domain; Cell Proliferation; Cells; Characteristics; Child; Data; Development; Dose; Ensure; Exhibits; Growth; Human; Hyperactive behavior; In Situ; In Vitro; Inhibitory Concentration 50; Lead; Malignant Bone Neoplasm; Measures; Mediator of activation protein; Molecular Conformation; Mus; Nutrient; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Phosphotransferases; Positioning Attribute; Property; Resistance; Signal Transduction; Site; Structure; Technology; Testing; TimeLine; Xenograft procedure; analog; angiogenesis; base; design; efficacy testing; improved; in vivo; in vivo Model; inhibitor/antagonist; insight; kinase inhibitor; novel; osteosarcoma; pre-clinical; programs; rapid growth; small molecule; tumor; tumor growth

DESCRIPTION (provided by applicant): Osteosarcoma is the most common primary bone cancer in children and adolescents. A key feature of osteosarcoma is their inherent high growth rates and the increased vasculature to enable rapid growth. Recent data implicate Ca2+/CaM-dependent protein kinase II (CaMKII), a major mediator of Ca2+ signaling, in both the unregulated proliferation of osteosarcoma and in the angiogenesis that supports its growth. Hyperactivity of CaMKII is associated with cell proliferation and resistance to apoptosis, while inhibition of CaMKII suppresses growth of osteosarcoma in animals. We aim to focus medicinal chemistry and preclinical development to generate improved CaMKII inhibitors that incorporate an allosteric site interaction. Our strategy is to start with a potent lead ATP site inhibitor of the kinase and extend it to interact with the helical inhibitory domain of the kinase. Biochemical analysis of inhibitors will measure their interaction with the inactive and active conformations. Medicinal chemistry will be used to develop inhibitors that span the catalytic site with preferential binding to the inactive conformation that is characteristic of allosteric interactions. While our current lead compounds can be used to test efficacy in osteosarcoma, the allosteric inhibitors will be more broadly useful because of greater selectivity. The best inhibitor will be tested for efficacy for its cellular action followed by efficacy on human osteosarcoma xenografted in mice. This will provide a clear path for a Phase II proposal to further improve its potency and other drug-like properties up to IND filing. CaMKII inhibitors may present a new paradigm in osteosarcoma-targeted agents that effectively treat the tumor by the dual mechanism of slowing its rapid growth and blocking its access to nutrients. PUBLIC HEALTH RELEVANCE: Osteosarcoma is the most common primary bone cancer in children and adolescents. A key feature of osteosarcomas is their inherent high growth rates and the increased vasculature to enable rapid growth. Recent data implicate Ca2+/CaM-dependent protein kinase II (CaMKII), a major mediator of Ca2+ signaling, in both the unregulated proliferation of osteosarcoma and in the increased blood vessel formation that upports its growth. We aim to modify an existing potent small molecule inhibitor of CaMKII to increase its selectivity, test it biochemically to ensure it has the desired mechanism of action, then test it on xenografted human osteosarcoma.

描述（由申请人提供）：骨肉瘤是儿童和青少年中最常见的原发性骨癌。骨肉瘤的一个关键特征是其固有的高生长速率和增加的脉管系统以实现快速生长。 最近的数据表明，Ca2+/CaM 依赖性蛋白激酶 II (CaMKII)（Ca2+ 信号传导的主要介质）参与骨肉瘤不受调节的增殖和支持其生长的血管生成。 CaMKII 的过度活跃与细胞增殖和细胞凋亡抵抗有关，而 CaMKII 的抑制可抑制动物中骨肉瘤的生长。我们的目标是专注于药物化学和临床前开发，以产生包含变构位点相互作用的改进的 CaMKII 抑制剂。我们的策略是从激酶的有效先导 ATP 位点抑制剂开始，并将其扩展到与激酶的螺旋抑制结构域相互作用。抑制剂的生化分析将测量它们与非活性和活性构象的相互作用。药物化学将用于开发跨越催化位点的抑制剂，并优先结合变构相互作用特征的非活性构象。虽然我们目前的先导化合物可用于测试骨肉瘤的疗效，但变构抑制剂由于具有更高的选择性，将具有更广泛的用途。将测试最好的抑制剂的细胞作用功效，然后测试其对小鼠异种移植的人骨肉瘤的功效。这将为二期提案提供一条清晰的道路，以进一步提高其效力和其他药物特性直至 IND 申请。 CaMKII 抑制剂可能为骨肉瘤靶向药物提供了一种新范例，通过减缓其快速生长和阻止其获取营养的双重机制来有效治疗肿瘤。 公共卫生相关性：骨肉瘤是儿童和青少年中最常见的原发性骨癌。骨肉瘤的一个关键特征是其固有的高生长速率和增加的脉管系统以实现快速生长。最近的数据表明，Ca2+/CaM 依赖性蛋白激酶 II (CaMKII)（Ca2+ 信号转导的主要介质）与骨肉瘤不受调节的增殖和支持其生长的血管形成增加有关。我们的目标是修改现有的有效 CaMKII 小分子抑制剂以提高其选择性，对其进行生化测试以确保其具有所需的作用机制，然后在异种移植的人骨肉瘤上进行测试。