Pro-Drug Enolase Inhibitors in Precision Oncology

抽象的。目前，主要抑癌基因的基因组缺失在癌症中是常见的事件 对于精确肿瘤学的目的，在治疗上仍然是不可操作的。我们的实验室开创了一种创新的 被称为侧枝致死性的治疗范式，即邻近编码关键基因的TSG基因 管家酶被巧合地删除了。我们发现新陈代谢的脆弱性是由 这种侧枝缺失可以通过抑制酶的多余异构体来进行治疗。 糖酵解酶烯醇化酶1纯合缺失的癌症就是这种结构的象征。 (ENO1)。由于糖酵解是一个基本的生物能量过程，ENO1纯合子缺失的癌症完全是 依靠ENO2进行糖酵解，确保细胞存活。抑制ENO2选择性地杀死 ENO1-纯合子基因删除了癌症，而不影响正常组织。对…起药理作用 针对这个漏洞，我们的实验室开发了一种ENO2首选的抑制剂HEX。作为对强者的见证 侧枝致死的治疗可行性，我们已经证明HEX能够完全根除ENO1- 小鼠脑内胶质母细胞瘤同型缺失型原位移植模型 非人灵长类动物。这种强大的抗肿瘤作用在胶质母细胞瘤和 谈谈附带致命性方法的威力。对抵押品致命性焦点的一种批评是它的范围： 在ENO1缺失的情况下，只有一小部分患者能够受益。要拓宽 侧枝致命性的治疗范围，这项提案将重点针对ENO1杂合子缺失的癌症， 约占所有人类癌症的20%。这将通过添加肿瘤亚型特异的PRO- 将药物部分连接到HEX上，以改善其传递。而ENO1杂合子缺失的癌症总体上是缺乏的 烯醇化酶，它们不会像ENO1纯合子缺失的癌症那样耗尽。因为十六进制是一种消极的 荷电分子，肿瘤亚型特异性前药物附着在HEX上不仅会增强其细胞 但也会提高其肿瘤的特异性。这两个特点结合在一起，将使药物剂量更低 提供足够大的治疗窗口来治疗ENO1杂合子缺失癌症的浓度 而不会扰乱正常组织。总体而言，这项建议利用理性亲药物设计的概念来 提高我们的核心ENO2抑制剂的特异性，以便我们可以扩大侧枝致死的治疗范围。

ABSTRACT. Genomic deletions of major tumor suppressor genes are frequent events in cancer yet presently remain therapeutically unactionable for the purpose of precision oncology. Our lab has pioneered an innovative therapeutic paradigm known as collateral lethality, whereby genes neighboring a TSG locus encoding a key housekeeping enzyme are coincidentally deleted. We discovered that the metabolic vulnerabilities arising from such collateral deletions may be therapeutically exploited through inhibition of the enzyme’s redundant isoform. Emblematic of this framework are cancers harboring homozygous deletion of the glycolytic enzyme Enolase 1 (ENO1). As glycolysis is an essential bioenergetic process, ENO1-homozygous deleted cancers are entirely reliant on the ENO2 to perform glycolysis and ensure the cellular viability. Inhibition of ENO2 selectively kills ENO1-homozygous deleted the cancers while leaving normal tissues unperturbed. To pharmacologically act on this vulnerability, our lab has developed an ENO2-preferred inhibitor, HEX. As testament to the strong therapeutic viability of collateral lethality, we have shown that HEX is capable of completely eradicating ENO1- homzoygous deleted intracranial orthotopic models of glioblastoma in mice at concentrations well-tolerated in non-human primates. Such robust anti-neoplastic effects are unprecedented in the context of glioblastoma and speak to the power of the collateral lethality approach. One critique of the focus of collateral lethality is its scope: in the case of ENO1-deletions, only a small percentage of patients would be able to benefit. To broaden the therapeutic reach of collateral lethality, this proposal will focus on targeting ENO1-heterozygous deleted cancers, which comprise ~20% of all human cancers. This will be accomplished by adding tumor subtype-specific pro- drug moieties onto HEX to improve its delivery. While ENO1-heterozygous deleted cancers are deficient in total Enolase, they are not nearly as depleted as ENO1-homozygous deleted cancers are. As HEX is a negatively charged molecule, tumor-subtype specific pro-drug attachment onto HEX will not only enhance its cell permeability but will also improve its tumor specificity. Together, these two traits will enable drug dosing at lower concentrations to afford a therapeutic window sufficiently large to treat ENO1-heterozygous deleted cancers without the perturbing normal tissues. Overall, this proposal leverages the concept of rational pro-drug design to improve the specific of our core ENO2 inhibitor so that we may widen the therapeutic reach of collateral lethality.