Identification of small molecule modulators of mitochondrial creatine kinase 1

项目摘要 受体酪氨酸激酶HER2在大约25%的乳腺癌中扩增或过表达， 与肿瘤的侵袭性和不良预后相关。虽然FDA批准的治疗曲妥珠单抗 已显示具有实质性临床获益，超过60%的HER2+癌症患者无应答 对它，几乎所有最初做出反应的人都不可避免地发展出后天的抵抗力，强调了现有的抵抗力。 对这种疾病的新治疗方法的未满足的需求。最近，我们发现了一种以前没有预料到的 HER2乳腺癌的代谢脆弱性，包括对曲妥珠单抗耐药的乳腺癌，过度依赖 线粒体肌酸激酶1（MtCK 1）和延伸的磷酸肌酸穿梭用于能量供应。我们 证明了已知的底物类似物环肌酸，由MtCK 1转化为磷酸环肌酸， 反过来作为磷酸肌酸途径的抑制剂，抑制曲妥珠单抗耐药的HER2 PDX肿瘤 生长，从而为小分子治疗干预提供概念证明。我们假设 抑制MtCK 1的药物将提供一种新的急需的抗HER2+肿瘤的防线 以及其他依赖MtCK 1存活的肿瘤，如EVI1+ AML。为了验证这一假设，我们提出 为了使用高通量大规模筛选（Aim 1）鉴定MtCK 1的一流小分子抑制剂， 命中确认（目标2）和命中分析和验证（目标3）。我们项目的完成将导致 鉴定抑制HER2癌症中磷酸肌酸穿梭的化合物。我们预计 知识、发展战略和化学探针将最终使创新的发展成为可能。 治疗方法来对抗HER2乳腺癌和潜在的其他癌症。

PROJECT SUMMARY The receptor tyrosine kinase HER2 is amplified or overexpressed in approximately 25% of breast cancers and is associated with tumor aggressiveness and poor prognosis. While the FDA-approved therapy trastuzumab has been shown to have substantial clinical benefit, more than 60% of patients with HER2+ cancer do not respond to it, and nearly all others who initially respond inevitably develop acquired resistance, underscoring the existing unmet need for new therapeutic approaches for this disease. Recently, we identified a previously unanticipated metabolic vulnerability of HER2 breast cancers, including the ones resistant to trastuzumab, in overreliance on mitochondrial creatine kinase 1 (MtCK1) and by extension creatine phosphate shuttle for energy supply. We demonstrated that a known substrate analog cyclocreatine, converted by MtCK1 into phosphocyclocreatine that in turn acts as an inhibitor of creatine phosphate pathway, suppresses trastuzunab-resistant HER2 PDX tumor growth, thus providing proof of concept for small molecule therapeutic intervention. We hypothesize that pharmacological agents inhibiting MtCK1 will offer a novel much needed line of defense against HER2+ tumors as well as other tumors dependent on MtCK1 for survival such as EVI1+ AML. To test this hypothesis we propose to identify first-in-class small molecule inhibitors of MtCK1 using high-throughput large-scale screening (Aim 1), hit confirmation (Aim 2) and hit profiling and validation (Aim 3). The completion of our project will result in identification of compounds inhibiting creatine phosphate shuttle in HER2 cancers. We expect that the knowledge, developed strategies, and chemical probes will ultimately enable the development of innovative therapeutic approaches to combat HER2 breast and potentially other cancers.