Understanding Efficacy and Fe(II)-Promoted Activation of 1,2,4-Trioxolanes in Cancer

项目摘要/摘要 综述：精准癌症医学的基础在于发现和开发至关重要的途径 对癌细胞来说，但对癌细胞来说是可有可无的。尽管存在这样的途径，但它们相对不常见。 更常见的情况是，癌细胞中激活的致癌途径对许多健康细胞也是必不可少的， 至少在一些成人组织中是这样。这一不幸的事实被称为低治疗指数(TI)，并使人沮丧 许多很有希望的癌症治疗方法。该项目旨在提高关键效应器的抑制物的TI Ras-MEK-ERK途径在最致命的人类癌症中的应用铁(II)激活药物和开发新的 Fe(II)可激活疗法。 背景：当癌细胞从正常向恶性转化时，它们会引起新陈代谢，并可能 药物方面的责任。他们处理最危险形式的铁，即铁(II)状态，尤其是 调节失调，导致不稳定铁池(LIP)增加。我们发明了一种优先靶向肿瘤的新方法 铁激活药物增加细胞对不稳定Fe2+的亲和力和浓度 共轭(FeADC)AP 专业人士 ACH是由临床验证的含Fe2+的1，2，4-三氧杂环己烷(TRX)部分激发的 依赖药理学。癌细胞随后激活FeADC，并暴露在有效载荷下。我们是 关注MEK抑制剂是因为1)它们的治疗指数低，2)它们在KRAS驱动的固体中有希望 肿瘤和3)KRAS癌基因驱动嘴唇增加到我们认为可以利用的水平。 方法：首先，我们将验证我们的改良的MEK抑制剂和改良的化疗药物在 KrasG12D驱动的自体免疫活性小鼠肺癌模型。然后我们将使用尖端技术 功能筛选以确定激活(连接)FeADC为活性有效载荷所需的细胞酶 在癌细胞中。然后，我们将进一步发展Fe(II)促进的1，2，4-三氧杂环己烷的活化，以诱导 一种特殊的细胞死亡形式，称为癌细胞中的铁性下垂。 影响：该项目的重点是改善靶向抑制剂的治疗指数，特别是在 缺乏服务的肿瘤；那些带有KRAS突变的肿瘤。我们有可能立即影响到一大片 通过我们灵活而强大的前药方法进行抗癌治疗。通过更好地理解 细胞内Fe(II)促进的1，2，4-三氧杂环己烷的活化机理，我们还可以开发新的类 称为FeADCs的抗癌化合物和利用铁下垂作为我们发育过程中的一个治疗终点 学习。

Project Summary/Abstract Summary: Precision cancer medicine’s foundation lies in discovering and exploiting pathways that are essential for cancer cells, but dispensable for cancer cells. While such pathways exist, they are relatively uncommon. Much more often the oncogenic pathways activated in cancer cells are essential for many healthy cells as well, at least in some adult tissue. This unfortunate fact is referred to as a low Therapeutic Index (TI), and frustrates many promising cancer treatments. This project seeks to improve the TI of inhibitors of critical effectors of the RAS MEK ERK pathway in the deadliest human cancers using Fe(II) activation of drugs and developing new, Fe(II) activatable therapies. Background: As cancer cells transform from normal to malignant, they incur metabolic and potentially pharmacologic liabilities. Their handling of iron in its most dangerous form, the Fe(II) state, is particularly dysregulated, leading to an increased labile iron pool (LIP). We invented a new way to preferentially target tumor cells based on increased avidity for, and elevated concentrations of labile Fe2+ with an Iron-Activated Drug Conjugate (FeADC) ap pro ach inspired by a clinically validated 1,2,4-trioxolane (TRX) moiety with Fe2+- dependent pharmacology. The cancer cell then activates the FeADC and is exposed to the payload. We are focusing on MEK inhibitors because 1) their therapeutic index is low, 2) they hold promise in KRAS-driven solid tumors and 3) the KRAS oncogene drives increases in the LIP to a level we think exploitable. Methods: First we will validate the efficacy of our modified MEK inhibitor and a modified chemotherapeutic in an autochthonous, immunocompetent model of mouse lung cancer driven by KrasG12D. We will then use cutting edge functional screening to identify the cellular enzymes needed to activate (uncage) the FeADC into active payloads in the cancer cell. We will then further develop the Fe(II)-Promoted Activation of 1,2,4-Trioxolanes to induce a specialized form of cellular death known as ferroptosis in cancer cells. Impact: This project focuses on a improving the therapeutic index of targeted inhibitors, especially in the most underserved tumors; those with KRAS mutations. We have the potential to immediately impact a large swath of anticancer therapeutics via our flexible and powerful prodrug approach. Through better understanding of the mechanisms of cellular Fe(II)-Promoted Activation of 1,2,4-Trioxolanes, we may also develop new classes of anticancer compounds called FeADCs and leveraging ferroptosis as a therapeutic endpoint in our developmental studies.