Targeting Casein Kinase 1d/e (CK1d/1e) in Cancer Therapeutics

项目摘要 我们研究团队的目标是优化和评估作为δ抑制剂的化合物， 酪蛋白激酶1（CK 1）的亚型。CK 1是单体丝氨酸/苏氨酸蛋白激酶， 调节不同的细胞过程，包括Wnt信号传导，DNA损伤反应和昼夜节律 节奏CK 1的异常调节与各种癌症、神经退行性疾病和 睡眠障碍重要的是，我们的研究团队结合了医学和合成药物方面的专业知识， 有机化学和新疗法的衍生（PI Dr. William Bauh），以及癌症治疗 遗传学和临床前治疗研究（共同PI博士约翰克利夫兰）和药物开发和抗 癌症激酶治疗（共同PI博士德里克Duckett）已经证明，我们的新的内部和高度 选择性和ATP竞争性CK 1抑制剂具有非常低的纳摩尔生化和抗癌活性， （黑色素瘤、乳腺癌和胶质母细胞瘤[GBM]）细胞效力。此外，体外遗传学研究， 黑色素瘤和三阴性乳腺癌细胞表明，我们的化合物的抗肿瘤活性是 与CK 1活性抑制一致，原位异种移植初步研究表明， CK 1抑制剂在体内具有有效的抗黑色素瘤和抗GBM活性。此外，NCI-60屏幕和 中空纤维试验表明，我们的CK 1抑制剂对其他人具有显著的效力， 癌症包括结肠癌、肺癌和肾癌。重要的是，我们的先导化合物通常没有毒性， 因为这些CK 1抑制剂不损害某些肿瘤类型或正常细胞的生长或存活 并且在临床前研究中，它们在长期21天BID给药中耐受良好。因此，我们假设， CK 1亚型是开发癌症治疗剂的高度有吸引力的靶点。在Aim中 1我们的CK 1抑制剂的类药物性质-包括脑渗透-将使用以下方法进行优化： 替代药物化学、DMPK和疗效筛选。我们将使用严格的研究操作计划 优先考虑将流入目标2和3中概述的研究的CK 1抑制剂。在目标2中，使用电池 我们将严格测试我们的先导化合物的抗癌活性， 优化的类似物仅仅是由于抑制CK 1 <$和/或CK 1 <$，或者其他生物学相关的 目标有助于其效力。使用小鼠模型，我们还测试了CK 1 <$和/或CK 1 <$在 突变BRaf驱动的黑色素瘤的发展。最后，在目标3中，将测试顶级化合物的 使用小鼠和人黑素瘤，人三阴性乳腺癌， 以及作为单一药剂和与常规疗法组合的原发性人GBM。我们 提交我们的研究团队将产生一系列新的，有效的和安全的抗癌药物， CK 1将作为广谱治疗剂用于治疗许多耐药恶性肿瘤。

Project Summary The goal of our research team is to optimize and evaluate compounds that are inhibitors of the delta and epsilon isoforms of casein kinase 1 (CK1¿/¿). CK1¿/¿ are monomeric serine/threonine protein kinases that regulate diverse cellular processes including Wnt signaling, the DNA damage response and circadian rhythms. Aberrant regulation of CK1¿/¿ is implicated in various cancers, and in neurodegenerative and sleep disorders. Importantly, our research team, which combines expertise in medicinal and synthetic organic chemistry and the derivation of novel therapeutics (PI Dr. William Roush), with those in cancer genetics and preclinical therapeutic studies (co-PI Dr. John Cleveland) and drug development and anti- cancer kinase therapeutics (co-PI Dr. Derek Duckett) has demonstrated that our new in-house and highly selective and ATP competitive CK1¿/¿ inhibitors have very low nanomolar biochemical and anti-cancer (melanoma, breast cancer and glioblastoma [GBM]) cell potency. Furthermore, ex vivo genetic studies in melanoma and triple-negative breast cancer cells indicate that the anti-tumor activity of our compounds is consistent with inhibition of CK1¿/¿ activity and pilot orthotopic xenograft studies have shown that our CK1¿/¿ inhibitors have potent anti-melanoma and anti-GBM activity in vivo. In addition, NCI-60 screens and hollow fiber assays have shown that our CK1¿/¿ inhibitors have remarkable potency against other human cancers that include colon, lung and renal cancer. Importantly, our lead compounds are not generally toxic, as these CK1¿/¿ inhibitors do not compromise the growth or survival of some tumor types or of normal cells and they are well tolerated in chronic 21 day BID dosing in pre-clinical studies. Thus, we hypothesize that the CK1¿/¿ isoforms are highly attractive targets for the development of cancer therapeutics. In Aim 1 the drug-like properties-including brain penetration-of our lead CK1¿/¿ inhibitors will be optimized using reiterative medicinal chemistry, DMPK, and efficacy screens. We will use a rigorous research operating plan to prioritize CK1¿/¿ inhibitors which will flow into studies outlined in Aims 2 and 3. In Aim 2, using a battery of genetic approaches, we will rigorously test whether the anti-cancer activity of our lead compounds and optimized analogs is solely due to inhibition of CK1¿ and/or CK1¿, or whether other biologically relevant targets contribute to their potency. Using mouse models we also test the roles of CK1¿ and/or CK1¿ in the development of mutant BRaf-driven melanoma. Finally, in Aim 3, top compounds will be tested for their anti-tumor efficacy using xenografts of mouse and human melanoma, human triple negative breast cancer, and of primary human GBM both as single agents and in combination with conventional therapies. We submit that our research team will generate a cast of new, potent and safe anti-cancer agents targeting CK1¿/¿ that will be useful as broad-spectrum therapeutics against a host of resistant malignancies.