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

描述(申请人提供)：骨肉瘤是儿童和青少年最常见的原发骨癌。骨肉瘤的一个关键特征是其固有的高生长率和增加的血管系统使其能够快速生长。最近的数据表明，钙/钙调素依赖的蛋白激酶II(CaMKII)是钙信号的主要中介，在骨肉瘤的无调控增殖和支持其生长的血管生成中都起着重要作用。CaMKII的高活性与细胞增殖和抗凋亡有关，而抑制CaMKII则抑制骨肉瘤的生长。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。我们的策略是从该激酶的一个有效的先导ATP位点抑制剂开始，并将其延伸到与该激酶的螺旋抑制域相互作用。抑制剂的生化分析将测量它们与非活性构象和活性构象的相互作用。药物化学将被用来开发跨越催化位置的抑制剂，优先结合到具有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以用于测试骨肉瘤的疗效，但变构抑制剂将因为更高的选择性而更广泛地发挥作用。最好的抑制剂将测试其细胞作用的有效性，然后是对移植于小鼠的人骨肉瘤的有效性。这将为第二阶段的提案提供一条明确的道路，以进一步提高其效力和其他类似药物的特性，直到IND申请。CaMKII抑制剂可能为骨肉瘤靶向药物提供了一种新的范例，这些药物通过减缓肿瘤的快速生长和阻止其获得营养的双重机制有效地治疗肿瘤。 公共卫生相关性：骨肉瘤是儿童和青少年最常见的原发骨癌。骨肉瘤的一个关键特征是其固有的高生长率和增加的血管系统使其能够快速生长。最近的数据表明，钙/钙调素依赖的蛋白激酶II(CaMKII)是钙信号的主要介导者，在骨肉瘤的不受调控的增殖和支持其生长的血管形成增加中都有作用。我们的目标是对现有的一种有效的CaMKII小分子抑制剂进行修饰，以提高其选择性，并对其进行生化测试，以确保其具有预期的作用机制，然后在人骨肉瘤异种移植瘤上进行测试。

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.