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

项目概要/摘要 精准癌症医学的基础在于发现和利用至关重要的途径 但对癌细胞来说却是一种抑制。虽然存在这种途径，但它们相对不常见。 更常见的是，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， 至少在某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）， 许多有希望的癌症治疗方法。该项目旨在提高关键效应物抑制剂的TI， RAS MEK ERK途径在最致命的人类癌症中使用Fe（II）激活药物并开发新的， Fe（II）活化疗法。 背景：随着癌细胞从正常向恶性转化，它们引起代谢和潜在的 药理学责任他们对最危险形式的铁的处理，即Fe（II）状态， 在某些情况下，铁库失调，导致不稳定铁库（LIP）增加。我们发明了一种新的方法， 基于对铁活化药物的不稳定Fe 2+的亲和力增加和浓度升高的细胞 结合物（FeADC）ap Pro 每一个都受到临床验证的具有Fe 2 +-的1，2，4-三恶茂烷（TRX）部分的启发。 依赖性药理学然后癌细胞激活FeADC并暴露于有效载荷。我们 专注于MEK抑制剂，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 3）KRAS癌基因驱动LIP增加到我们认为可利用的水平。 方法：首先，我们将验证我们改良的MEK抑制剂和改良的化疗剂在肿瘤中的疗效。 由KrasG 12 D驱动的小鼠肺癌的原位免疫活性模型。我们将使用尖端技术 功能筛选以鉴定将FeADC活化（释放）成活性有效载荷所需的细胞酶 在癌细胞中。然后，我们将进一步开发Fe（II）促进的1，2，4-三恶茂烷活化，以诱导 一种特殊的细胞死亡形式，称为癌细胞中的铁凋亡。 影响：该项目的重点是提高靶向抑制剂的治疗指数，特别是在大多数情况下， 有KRAS突变的肿瘤。我们有可能立即影响一大片 通过我们灵活而强大的前药方法，通过更好地了解 细胞Fe（II）促进的1，2，4-三氧戊环活化的机制，我们也可能开发新的类别， 抗癌化合物称为FeADC和利用铁凋亡作为治疗终点，在我们的发展 问题研究

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.