Therapeutic Targeting of Casein Kinase-1-delta in Primary and Metastatic Breast Cancer

酪蛋白激酶-1-δ 在原发性和转移性乳腺癌中的治疗靶向

• 批准号: 10524031
• 负责人: John L. Cleveland
• 金额: $ 71.49万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-04 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10524031
• 关键词: ABCB1 gene; Acute; Apoptosis; Basal Cell; Binding Proteins; Biochemical; Biological Assay; Blood; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Patient; Breast Cancer Prevention; Breast Oncology; Breast cancer metastasis; Cancer Cell Growth; Casein Kinase Iepsilon; Cell Survival; Cell model; Cells; Chemoresistance; Chronic; Clinic; Complement; Complex; Cues; DNA Damage; Data; Dependence; Disease; Distant; Dose; Drug Combinations; Drug Kinetics; Extravasation; Genetic; Genetic Transcription; Growth; Human; Immune Evasion; Impairment; Interstitial Collagenase; Invaded; Lung; MMP2 gene; MMP9 gene; Malignant Neoplasms; Matrix Metalloproteinases; Mediating; Metastatic Neoplasm to the Lung; Metastatic breast cancer; Microsomes; Mus; Neoplasm Circulating Cells; Neoplasm Metastasis; Organ; Pathway interactions; Patient-derived xenograft models of breast cancer; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Play; Process; Prognosis; Property; Protein Isoforms; Protein-Serine-Threonine Kinases; Proteins; Proteomics; Recurrence; Refractory; Reporter; Reporting; Repression; Research; Resistance; Role; Safety; Serine; Signal Transduction; Site; Snails; Stem Cell Factor; Structure; Testing; Therapeutic; Tissues; Treatment Failure; Tumorigenicity; analog; beta catenin; bone; cancer clinical trial; cancer stem cell; casein kinase I; chemotherapy; design; efficacy testing; epithelial to mesenchymal transition; fluorescence imaging; genetic approach; improved; in vivo; inhibitor; lead candidate; loss of function mutation; lung metastatic; malignant breast neoplasm; metastatic process; migration; mouse model; mutant; nanomolar; neoplastic cell; novel; novel therapeutics; overexpression; phosphoproteomics; prevent; programs; resistance mechanism; safety assessment; self-renewal; side effect; small molecule; small molecule inhibitor; stem cell self renewal; synergism; targeted treatment; therapeutic target; transcription factor; transcriptome sequencing; treatment response; triple-negative invasive breast carcinoma; tumor; tumor progression

Our Multi-PI research team recently reported that the delta isoform of casein kinase-1 (CK1δ) is amplified and/or overexpressed in over a third of all breast cancers, and that CK1δ activation is especially manifest in refractory forms of breast cancer such as triple-negative breast cancer (TNBC) that lacks targeted therapies. Further, we established that silencing CK1δ, or inhibition of CK1δ kinase activity with our nanomolar potent, highly selective small molecule dual inhibitor of CK1δ and CK1ε, specifically compromises the growth, survival and invasion of breast cancer cells that overexpress CK1δ. Notably, CK1δ inhibition also provokes tumor regression of TNBC, including lung metastatic TNBC and basal-like PDX breast cancer models, and without any overt side effects. Finally, we demonstrated that CK1δ inhibition disables WNT/β-catenin signaling, a frequently activated yet heretofore undruggable pathway that is activated in a broad cast of human malignancies. Importantly, our new studies suggest roles for CK1δ in TNBC metastasis, where we have now shown that CK1δ signaling is necessary to sustain the expression of: (i) transcription factors that direct the epithelial to mesenchymal transition (EMT), including Zeb1 and Snail2; (ii) matrix metalloproteinases-1 (MMP1), MMP2 and MMP9 that control TNBC cell invasion; and (iii) the breast cancer stem cell (BCSC) factors Bmi1 and Sox9 that control self renewal. Finally, we have shown that our CK1δ inhibitors have synergy with select in-clinic DNA-damaging chemotherapies used to treat TNBC. Collectively, these data support the hypotheses that CK1δ is a driver of breast cancer metastases and that targeting CK1δ will block and improve treatment of metastatic triple negative breast cancer. Accordingly, in Aim1 we will use an iterative and rigorous research operating plan (ROP) to improve the pharmacokinetic (PK) properties of our dual CK1δ/CK1ε inhibitors, and will develop and test the efficacy of CK1δ-selective inhibitors, to deliver safety assessment candidates suitable for subsequent IND-enabling studies. This ROP includes tests of synergy of our inhibitors with in-clinic agents used to treat TNBC. Further, using genetic approaches and our CK1δ inhibitors, in Aim 2 we will test roles for CK1δ in each step of the metastatic cascade, including intravasation, extravasation, latency and/or establishment at the secondary site. Finally, in Aim 3, using phosphoproteomics, activity-based proteomic profiling, and RNA-seq we will identify and test the roles of downstream effectors of CK1δ in controlling TNBC metastasis, and the EMT, MMPs and BCSC targets of CK1δ signaling. These studies, and those in TNBC that we have generated that are resistant to our CK1δ/ε inhibitors, will define acute and chronic changes in components of the kinome that could be exploited for combination studies, to improve therapeutic response and block the emergence of resistance. We submit our research program will establish CK1δ as a vulnerability to target metastatic triple negative breast cancer, and that the small molecule CK1δ/ε or CK1δ inhibitors that we develop will have a major impact in the breast oncology clinic.

我们的多PI研究小组最近报告说，酪蛋白激酶-1的增量亚型(CK1δ)被扩增 和/或在超过三分之一的乳腺癌中过度表达，并且CK1δ激活在 难治性乳腺癌，如缺乏针对性治疗的三阴性乳腺癌(TNBC)。 此外，我们还证实，沉默CK1δ，或用我们的纳摩尔效力抑制CK1δ激酶活性， 高选择性小分子细胞角蛋白1δ和细胞角蛋白1ε双重抑制剂，特异性地影响细胞的生长、存活 和过度表达CK1δ的乳腺癌细胞的侵袭。值得注意的是，抑制CK1δ也会引发肿瘤 TNBC的消退，包括肺转移的TNBC和基底样PDX乳腺癌模型，以及无 任何明显的副作用。最后，我们证明了CK1的δ抑制使WnT/β-连环蛋白信号失活。 在广泛的人类中被激活的频繁激活的但迄今为止不可药物的途径 恶性肿瘤。重要的是，我们的新研究表明，ck1δ在肿瘤转移中的作用，我们现在已经 研究表明，CK1的δ信号对于维持下列转录因子的表达是必要的：(I)转录因子引导 上皮间充质转化(EMT)，包括ZEB1和Snail2；(Ii)基质金属蛋白酶-1 (3)乳腺癌干细胞(BCSC)； 控制自我更新的Bmi1和Sox9因子。最后，我们证明了我们的ck1δ抑制剂具有协同作用。 使用选择性的临床DNA损伤化疗药物治疗TNBC。总的来说，这些数据支持 假设CK1δ是乳腺癌转移的驱动因素，靶向CK1δ将阻断和 提高转移性三阴性乳腺癌的治疗水平。因此，在Aim1中，我们将使用迭代 和严格的研究操作计划(ROP)来改善我们的DUAL的药代动力学(PK)特性 CK1δ/CK1ε抑制剂，并将开发和测试CK1δ选择性抑制剂的疗效，以提供安全性 适合后续IND学习的评估候选人。此ROP包括对以下各项的协同测试 我们的抑制剂与临床药物一起用于治疗TNBC。此外，使用遗传方法和我们的CK1δ 在目标2中，我们将测试CK1δ在转移级联反应的每一步中的作用，包括血管内注射， 二次部位的渗出、潜伏期和/或建立。最后，在目标3中，使用磷酸蛋白质组学， 基于活性的蛋白质组学和rna-seq我们将识别和测试下游效应器的作用。 CK1δ在控制肿瘤转移中的作用以及CK1δ信号转导的靶点。这些 研究，以及我们在TNBC中产生的对CK1δ/ε抑制剂具有耐药性的研究，将定义急性 以及可以用于组合研究的亲属组组成的慢性变化，以改善 治疗反应和阻断耐药的出现。我们提交了我们的研究计划将建立 CK1δ易被认为是转移性三阴性乳腺癌的靶点，而小分子CK1δ/ε 或者我们开发的CK1δ抑制剂将在乳腺肿瘤临床上产生重大影响。

项目成果

Structure-Based Development of Isoform-Selective Inhibitors of Casein Kinase 1ε vs Casein Kinase 1δ.

• DOI: 10.1021/acs.jmedchem.2c01180
• 发表时间: 2023-06-08
• 期刊: JOURNAL OF MEDICINAL CHEMISTRY
• 影响因子: 7.3
• 作者: Choi, Jun Yong;Noguchi, Yoshihiko;Alburger, James M.;Bayle, Simon;Chung, Eugene;Grant, Wayne;Chaikuad, Apirat;Knapp, Stefan;Duckett, Derek R.;Roush, William R.
• 通讯作者: Roush, William R.