Identification of small molecule modulators of mitochondrial creatine kinase 1

项目总结 受体酪氨酸激酶HER2在大约25%的乳腺癌中扩增或过度表达， 与肿瘤侵袭性和预后不良有关。而FDA批准的曲妥珠单抗已经 已经被证明有很大的临床益处，超过60%的HER2+癌症患者没有反应 对于它，以及几乎所有其他最初做出反应的人，不可避免地会产生后天抵抗力，这突显了现有的 对这种疾病的新治疗方法的需求尚未得到满足。最近，我们发现了一种以前没有预料到的 HER2乳腺癌，包括对曲妥珠单抗耐药的乳腺癌，过度依赖于 线粒体肌酸激酶1(MtCK1)和延伸的肌酸磷酸穿梭提供能量。我们 证明了一种已知的底物类似物环肌酸，由MtCK1转化为磷酸环肌酸，该磷酸环肌酸 反过来作为磷酸肌酸途径的抑制物，抑制曲妥珠那布耐药的HER2 PDX肿瘤 生长，从而为小分子治疗干预提供了概念证明。我们假设 抑制MtCK1的药物将提供一条对抗HER2+肿瘤的新的、急需的防线 以及其他依赖MtCK1生存的肿瘤，如EVI1+AML。为了检验这一假设，我们提出了 使用高通量大规模筛选(目标1)鉴定MtCK1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 抑制HER2肿瘤中磷酸肌酸穿梭的化合物的鉴定。我们预计， 知识、制定的战略和化学探测最终将使创新的发展成为可能 与HER2乳腺癌和其他潜在癌症作斗争的治疗方法。

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.