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

描述（由申请人提供）：骨肉瘤是儿童和青少年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率和增加的血管系统使其能够快速生长。 最近的数据牵连钙/钙调素依赖性蛋白激酶II（CaMKII），钙信号的主要介质，在两个不受调节的骨肉瘤增殖和血管生成，支持其生长。 CaMKII的高活性与细胞增殖和抗凋亡相关，而抑制CaMKII则抑制动物骨肉瘤的生长。我们的目标是专注于药物化学和临床前开发，以产生改进的CaMKII抑制剂，将变构位点相互作用。我们的策略是从激酶的一个有效的前导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，其优先结合到非活性构象，这是变构相互作用的特征。虽然我们目前的先导化合物可用于测试在骨肉瘤中的功效，但变构抑制剂将因其更大的选择性而更广泛地使用。将测试最佳抑制剂的细胞作用功效，然后测试其对小鼠中异种移植的人骨肉瘤的功效。这将为II期提案提供一条明确的道路，以进一步提高其效力和其他药物性质，直至IND申请。CaMKII抑制剂可能为骨肉瘤靶向药物提供新的范例，通过减缓其快速生长和阻断其获得营养的双重机制有效治疗肿瘤。 公共卫生相关性：骨肉瘤是儿童和青少年最常见的原发性骨癌。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，以实现快速生长。最近的数据牵连钙/钙调素依赖性蛋白激酶II（CaMKII），钙信号的主要介质，在两个不受管制的骨肉瘤增殖和血管形成，支持其生长。我们的目标是修改现有的有效的小分子抑制剂CaMKII，以增加其选择性，测试它的生化，以确保它具有所需的作用机制，然后测试它对异种移植的人骨肉瘤。

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.