INHIBITORS OF CELLULAR TRANSPORTERS FOR THE TREATMENT OF TNBC

治疗TNBC的细胞转运蛋白抑制剂 摘要 三阴性乳腺癌(TNBC)是由细胞的受体状态定义的。TNBC不表示 雌激素、孕激素或HER-2受体。据估计，全球有100万女性被诊断出患有 每年都会患乳腺癌。TNBC是最致命的乳腺癌亚型，约占乳腺癌总数的15%。 乳腺癌诊断和约25%的乳腺癌相关死亡。30%的患者的中位生存期 与TNBC的合作期限为1年。TNBC更多发生在60岁以下的女性，尤其是 非裔美国人后裔，以及那些拥有BRAC1突变的人。75%(75%) 患有BRAC1突变的乳腺癌的女性将患上TNBC。TNBC的临床应用较差 结果是因为它高度转移，对化疗耐药，并且缺乏有效的治疗选择。 尼罗吉酮的方法是开发小分子MCT1/MCT4双重抑制剂来分流糖酵解， 阻断代谢共生，防止转移，有效治疗TNBC。一种新型的铅分子(NGT- 008)已经合成，并在体外和体内先导实验中进行了评价。初步数据 表明NGT-008对TNBC细胞株MDA-MB-231和MDA-MB-468具有良好的抑制作用。 良好的物理化学性质，合理的小鼠药代动力学曲线，适中的体内疗效。 NGT-008对包括肌肉细胞在内的几种正常细胞株，即使在10微米的浓度下也没有细胞毒作用 已知的表达MCT的基因。在本申请中，我们建议进一步表征NGT-008及其 通过实现以下目标来优化模拟： (1)通过迭代合成和迭代合成开发具有改进的药代动力学和药效的NGT-008类似物 MCT1和MCT4的同源模型有助于发现新的改进的先导化合物以增加 活体功效 (2)将体外细胞毒性研究扩展到其他TNBC细胞系 (3)对优化后的类似物在小鼠移植瘤模型中的体内药效进行评价。 建立3D共培养体系。 拟议的工作将确定NGT-008或其优化的类似物作为一种新的治疗方法的可行性 治疗TNBC的药物。下一步将是在更多的体内研究中评估优化的类似物 (原位模型、PDX模型、剂量反应、给药方案、毒理学评估等)如所确定的 根据AIMS 1、2和3的结果来提名临床前候选人。这将是第二阶段的一部分 申请。

INHIBITORS OF CELLULAR TRANSPORTERS FOR THE TREATMENT OF TNBC Abstract Triple Negative Breast Cancer (TNBC) is defined by the receptor status of the cells. TNBC does not express estrogen, progesterone, or Her-2 receptors. It is estimated that 1 million women worldwide are diagnosed with breast cancer each year. TNBC is the most deadly sub-type of breast cancer, accounting for ~15% of the breast cancer diagnoses and ~25% of breast cancer-related deaths. Median survival for 30% of the patients with TNBC is 1 year. TNBC arises more frequently in women younger than 60 years of age, particularly of African-American descent, and those who possess the BRAC1 mutation. Seventy-five percent (75%) of women, who have breast cancer with the BRAC1 mutation, will develop TNBC. TNBC has poor clinical outcomes because it is highly metastatic, resistant to chemotherapy, and lacks effective treatment options. Nirogyone’s approach is to develop small molecule MCT1/MCT4 dual inhibitors to shunt glycolysis, block metabolic symbiosis, prevent metastasis, and effectively treat TNBC. A novel lead molecule (NGT- 008) has already been synthesized, and evaluated in in vitro and in vivo pilot experiments. Preliminary data demonstrates that NGT-008 exhibits good potency against a TNBC cell lines, MDA-MB-231 and MDA-MB-468, good physicochemical properties, reasonable mouse pharmacokinetic profile, and modest in vivo efficacy. NGT-008 showed no cytotoxicity even at 10µM against several normal cell lines including muscle cells which are known to express MCTs. In this application, we propose to further characterize NGT-008 and its optimized analogs by conducting the following AIMS: (1) Develop analogs of NGT-008 with improved pharmacokinetic profile and potency by iterative synthesis and homology models of MCT1 and MCT4 to aid in the discovery of new improved lead compounds to increase in vivo efficacy (2) Extend in vitro cytotoxicity studies to other TNBC cell lines (3) Evaluate the in-vivo efficacy of the optimized analog in a mouse xenograft model of MDA-MB-231 while establishing a 3D co-culture system. The proposed work will determine the feasibility of NGT-008 or its optimized analog as a novel therapeutic agent to treat TNBC. Next steps will be to evaluate an optimized analog in additional in-vivo studies (orthotopic models, PDX models, dose response, dosing regimen, toxicology assessment, etc.) as determined by results from AIMS 1, 2, and 3 in order to nominate a pre-clinical candidate. This will be a part of Phase II application.