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最常见的原发性骨癌。骨肉瘤的一个关键特征是它们固有的高增长率和增加的脉管系统以实现快速生长。 最近的数据暗示Ca2+/CAM依赖性蛋白激酶II（CAMKII）是Ca2+信号传导的主要介体，在不调节的骨肉瘤增殖和支持其生长的血管生成中。 CaMKII的多动症与细胞增殖和对凋亡的抗性有关，而CaMKII的抑制作用抑制了动物中骨肉瘤的生长。我们旨在将药物化学和临床前发育集中在融合变构相互作用的CAMKII抑制剂中，以产生改进的CAMKII抑制剂。我们的策略是从激酶的有效铅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。对抑制剂的生化分析将测量其与非活动和活跃构象的相互作用。药物化学将用于开发跨催化部位的抑制剂，其优先结合与变构相互作用的特征的不活跃构象。尽管我们当前的铅化合物可用于测试骨肉瘤的功效，但由于选择性更高，变构抑制剂将更广泛地有用。最好的抑制剂将通过其细胞作用进行疗效，然后对小鼠中人​​骨肉瘤的功效进行疗效。这将为II期提案提供一条清晰的途径，以进一步提高其效力和其他类似药物的特性。 CAMKII抑制剂可能会在靶向骨肉瘤的剂中提出新的范式，该剂量通过减慢其快速生长并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性骨癌。骨肉瘤的一个关键特征是它们固有的高增长率和增加的脉管系统以实现快速生长。最近的数据暗示Ca2+/CAM依赖性蛋白激酶II（CAMKII）是Ca2+信号传导的主要介体，在骨肉瘤的不受调节的增殖和增加的血管形成中，都可以增强其生长。我们旨在修改CAMKII的现有有效的小分子抑制剂，以提高其选择性，以生化测试以确保其具有所需的作用机理，然后对异种移植的人骨肉瘤进行测试。