Targeted Depalmitoylation for the Treatment of NRas-Driven Melanoma

项目摘要 意义：黑色素瘤是最致命的皮肤癌，代表着日益增长的经济负担， 虽然早期黑色素瘤通常可以手术治疗，但晚期黑色素瘤的治疗方法 这种疾病的形式是严重缺乏。随着黑色素瘤的发病率持续上升，我们必须制定 新的有效的治疗方法。最具攻击性的黑色素瘤是由一种突变引起的， 在20%的患者中存在。虽然NRas是一个有吸引力的治疗靶点， 在黑色素瘤中，由于其表面缺乏合适的结合口袋，已经证明其非常难以给药。 这种局限性阻碍了NRas靶向治疗的发展。目标：解决未得到满足的问题 为了满足NRAS靶向药物的需要，我们将靶向NRAS的一个以前被忽视的区域，即其S-棕榈酰化。 C-末端高变区。许多研究已经证实，NRas棕榈酰化是其 癌症信号活性。为了利用NRas的这一特性，我们开发了一类新的脱棕榈酰化的 分子（DPALMs），其化学选择性地从活细胞中的蛋白质裂解S-棕榈酰基。初步 数据：我们已经鉴定了一组DPALM先导化合物，其在生活中优先脱棕榈酰化NRas。 细胞此外，我们发现DPALMs可以抑制下游Ras信号通路，并优先杀死 NRas突变体与非NRas突变体细胞系，突出了它们的治疗潜力。具体目标：我们将 优化我们的先导化合物的效力和选择性，以生成适用于临床前测试的DPALM 和IND赋能研究。在SPECIFIC AIM 1中，我们将使用联合合成生成一组优化的DPALM 和筛选工作。将使用模块化和稳健的合成策略来产生新的化合物， 然后在经验证的试验中筛选NRAS脱棕榈酰化活性和选择性。具体目标 2，我们将评估优化的DPALM在NRas驱动的黑素瘤细胞系中的功效。化合物将 测试了它们在NRAS驱动的细胞与对照细胞中优先抑制生长和诱导细胞死亡的能力 线拟议的研究将使高度NRAS选择性DPALM的开发成为可能，并加速 这种用于治疗黑色素瘤和其他几种癌症的靶向治疗的商业化具有很高的风险。 NRAS突变率。

PROJECT SUMMARY Significance: Melanoma is the deadliest form of skin cancer and represents a growing economic burden and health concern in the U.S. While early-stage melanoma can often be treated surgically, therapies for advanced forms of the disease are severely lacking. As rates of melanoma continue to rise, it is imperative that we develop novel and effective treatments for this disease. The most aggressive form of melanoma results from a mutation in the small GTPase NRas and presents in 20% of patients. While NRas is an attractive therapeutic target in melanoma, it has proven notoriously difficult to drug due to the lack of suitable binding pockets on its surface. This limitation has prevented the development of NRas-targeted therapies. Objective: To address the unmet need for NRas-targeted drugs, we will target a previously overlooked region of NRas, the S-palmitoylation of its C-terminal hypervariable region. Numerous studies have confirmed that NRas palmitoylation is required for its cancer signaling activity. To exploit this feature of NRas, we have developed a novel class of Depalmitoylating Molecules (DPALMs) which chemoselectively cleave S-palmitoyl groups from proteins in live cells. Preliminary Data: We have identified a set of DPALM lead compounds which preferentially depalmitoylate NRas in living cells. Furthermore, we found that DPALMs can inhibit downstream Ras signaling pathways and preferentially kill NRas-mutant versus non-NRas-mutant cell lines, highlighting their therapeutic potential. Specific Aims: We will optimize the potency and selectivity of our lead compounds to generate a DPALM suitable for preclinical testing and IND enabling studies. In SPECIFIC AIM 1, we will generate a set of optimized DPALMs using joint synthesis and screening efforts. A modular and robust synthetic strategy will be used to generate new compounds which will then be screened for NRas depalmitoylation activity and selectivity in a validated assay. In SPECIFIC AIM 2, we will evaluate the efficacy of optimized DPALMs in NRas-driven melanoma cell lines. Compounds will be tested for their ability to preferentially inhibit growth and induce cell death in NRas-driven versus control cell lines. The proposed studies will enable the development of a highly NRas-selective DPALM and accelerate the commercialization of this targeted therapy for the treatment of melanoma and several other cancers with high rates of NRas-mutations.