Targeting the dependency of cancer cells on the sirtuin SIRT5

由于癌症的异质性和肿瘤的免疫原性，新的抗癌剂仍然有很大的需求。 对现有药物产生耐药性。这项由三位PI（Richard Cerione， Hening Lin和Robert韦斯）旨在建立SIRT 5抑制作为治疗癌症的新策略。SIRT 5是一个 已知具有NAD+依赖性蛋白质赖氨酸脱酰作用的酶的沉默调节蛋白家族成员 活动它们在生理学中起着重要作用，包括转录、代谢和 寿命我们是第一个发现SIRT 5，一种具有非常弱的脱乙酰化活性的线粒体sirtuin， 优选水解带负电荷的酰基赖氨酸修饰，如琥珀酰和丙二酰赖氨酸， proteins.我们和其他人已经建立了赖氨酸琥珀酰化作为一种丰富的翻译后修饰 影响许多代谢酶。此外，我们最近获得了令人兴奋的初步数据， SIRT 5缺失会损害小鼠的肿瘤发生和转移。在细胞水平上，我们发现， SIRT 5的失活抑制了癌细胞的锚定非依赖性生长，但在某些情况下， 对常规单层培养物中增殖的影响。我们假设SIRT 5介导的调节 代谢是恶性转化和获得诸如锚定的性质所必需的- 独立生长和入侵性。拟议研究的一个目标是了解 SIRT 5在癌细胞以及肿瘤微环境中的分子功能。成功完成 这一目标的实现可能会揭示癌症对代谢改变的独特依赖性， 可以帮助开发治疗癌症的新疗法。基于小说的发现 由于SIRT 5的酶活性，我们已经开发了SIRT 5的小分子抑制剂，其具有非常高的选择性， 不抑制其他sirtuins。一些抑制剂在细胞培养中显示出有希望的抗癌活性， 小鼠模型。该提议的另一个目标是开发另外的SIRT 5抑制剂，其具有改善的体内活性。 在小鼠模型中对抗癌症的功效。我们非常兴奋的是， 该项目是基于对酶活性和生物化学的深刻理解， SIRT 5，再加上培养细胞和小鼠的严格生物学分析。

New anticancer agents are still in great demand due to the heterogeneous nature of cancer and the development of resistance to existing drugs. This collaborative proposal by three PIs (Richard Cerione, Hening Lin, and Robert Weiss) aims to establish SIRT5 inhibition as new strategy to treat cancers. SIRT5 is a member of the sirtuin family of enzymes that are known to have NAD+-dependent protein lysine deacylation activities. They play important roles in physiology, including the regulation of transcription, metabolism, and lifespan. We were the first to discover that SIRT5, a mitochondrial sirtuin with very weak deacetylation activity, prefers to hydrolyze negatively charged acyl lysine modifications, such as succinyl and malonyl lysine, from proteins. We and others have established lysine succinylation as an abundant post-translational modification that affects many metabolic enzymes. Moreover, we have recently obtained exciting preliminary data showing that SIRT5 deletion impairs tumorigenesis and metastasis in mice. At the cellular level, we found that inactivating SIRT5 inhibits the anchorage-independent growth of cancer cells, but in some cases has little effect on proliferation in conventional monolayer cultures. We hypothesize that SIRT5-mediated regulation of metabolism is required for malignant transformation and the acquisition of properties like anchorage- independent growth and invasiveness. One objective of the proposed studies is to understand the detailed molecular functions of SIRT5 in cancer cells, as well as in the tumor microenvironment. Successful completion of this goal is likely to shed light on the unique dependencies of cancers on metabolic alterations, knowledge that can help the development of novel therapeutics for treating cancer. Based on the discovery of the novel enzymatic activity of SIRT5, we have developed small molecule inhibitors of SIRT5 that are very selective and do not inhibit other sirtuins. Some of the inhibitors have shown promising anticancer activity in cell culture and mouse models. Another goal of this proposal is to develop additional SIRT5 inhibitors with improved in vivo efficacies against cancer in mouse models. We are very excited about the robust translational potential of the project, which is based on strong fundamental understanding of the enzymatic activity and biochemistry of SIRT5, coupled with rigorous biological analyses in cultured cells and mice.