Development of a dual MDM2/XIAP inhibitor with a high therapeutic index for childhood cancers

开发针对儿童癌症具有高治疗指数的双重 MDM2/XIAP 抑制剂

• 批准号: 10087056
• 负责人: Zhongzhi Wu
• 金额: $ 5.5万
• 依托单位: SEAK THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10087056
• 关键词: Acute Lymphocytic Leukemia; Antineoplastic Agents; Apoptosis; BIRC4 gene; Binding; Biochemical; Brain Neoplasms; Cancer Patient; Cell Survival; Cellular Assay; Childhood Cancer Treatment; Clinical Trials; Collaborations; Development; Disease Progression; Drug Kinetics; Drug Targeting; Foundations; Future; G-Protein-Coupled Receptors; Goals; Internal Ribosome Entry Site; Ion Channel; Isomerism; Legal patent; MDM2 gene; Malignant Childhood Neoplasm; Maps; Maximum Tolerated Dose; Medical; Names; Neuroblastoma; Non-Small-Cell Lung Carcinoma; Normal Cell; Optics; Pharmaceutical Preparations; Phase; Physiological; Proteins; Radiation therapy; Refractory; Risk; Small Business Innovation Research Grant; Solid; Structure; TP53 gene; Therapeutic; Therapeutic Index; Tissues; Toxic effect; Treatment outcome; Work; Xenograft Model; acute toxicity; analog; anti-cancer; anticancer activity; cancer cell; cancer type; chemotherapy; clinical candidate; improved; in vivo; inhibitor/antagonist; leukemia; malignant breast neoplasm; mouse model; novel anticancer drug; overexpression; phase 1 study; scaffold; side effect; small molecule; success; treatment strategy; tumor

PROJECT SUMMARY Acute lymphoblastic leukemia (ALL) and neuroblastoma (NB) are the most common cancers in children. Currently treatment options are often associated with severe side effects. Therefore, there is a strong unmet medical need to develop targeted-drugs with higher therapeutic indexes for improved treatment outcome. The oncoproteins MDM2 and XIAP are important cell-survival proteins in tumors. Elevated MDM2 and XIAP expression is associated with disease progression and poor treatment outcomes. They represent very attractive cancer drug targets. While several MDM2-p53 and XIAP inhibitors exist, none of them made to the market yet. A recent collaboration at UTHSC and Emory led to the discovery and patenting of the small molecule MX69- 52 as a MDM2/XIAP dual inhibitor. MX69-52 binds to the MDM2 RING domain and disrupts its interaction with XIAP IRES, resulting in simultaneous inhibition of both MDM2 and XIAP, leading to cancer cell apoptosis. MX69- 52 has an MTD ≥200 mg/kg and is effective against leukemia xenograft models at 15 mg/kg, suggesting a large therapeutic index. SEAK Therapeutics licensed this patented scaffold and aims to develop the most potent isomer within the isomeric mixture MX69-52, namely MX69-52d, as a more effective drug for pediatric cancers. SEAK Therapeutics proposes in this Phase I SBIR to characterize and de-risk MX69-52d as a viable clinical candidate and to provide proof of concept for this approach. Aim 1. Generate sufficient amounts of the most potent optical isomer MX69-52d and determine its absolute structure. Milestones: (1) produce 500 mg of MX69-52d (purity ≥ 98%); (2) unambiguously determined the absolute structure of MX69-52d to enable future development of a stereo-specific synthesis. Aim 2. Confirm MDM2/XIAP dual inhibition by MX69-52d and evaluate its potential off-target effects against a panel of physiologically important targets. We will confirm that MX69-52d maintains its mode of action similar to that of its isomeric mixture MX69-52. We will also map its potential off-target effects using Cerep’s Safety47 panel. Milestones: (3) confirmed dual MDM2/XIAP inhibitory abilities of MX69-52d in both biochemical and cellular assays; (4) identified potential interactions at 10 µM on physiologically important targets (e.g., GPCRs, ion channels, transporters) to further de-risk MX69-52d. Aim 3. Determine maximum tolerated dose (MTD) and pharmacokinetic (PK) parameters of MX69-52d, evaluate its anticancer activities in xenograft models, and assess its potential in vivo toxicity to normal cells/tissues. We will evaluate the improved efficacy and therapeutic index of MX69-52d using two mouse models of pediatric cancers. Milestones: (5) the MTD of MX69-52d (≥200 mg/kg) and PK parameters; (6) demonstrated anti-cancer efficacy without acute toxicities at ≤20 mg/kg. Success of this work will set the stage for a Phase II SBIR focusing on the development of MX69-52d or an improved analog through pre-IND studies, with the goal to develop a more effective drug for pediatric cancers.

项目概要 急性淋巴细胞白血病（ALL）和神经母细胞瘤（NB）是儿童最常见的癌症。 目前的治疗选择通常与严重的副作用相关。因此，存在着强烈的未满足 医学界需要开发具有更高治疗指数的靶向药物以改善治疗效果。 癌蛋白 MDM2 和 XIAP 是肿瘤中重要的细胞生存蛋白。 MDM2 和 XIAP 升高 表达与疾病进展和不良治疗结果相关。他们代表着非常有吸引力 癌症药物靶点。虽然存在多种 MDM2-p53 和 XIAP 抑制剂，但尚未投放市场。 UTHSC 和埃默里大学最近的一项合作导致了小分子 MX69 的发现并获得了专利 52 作为 MDM2/XIAP 双重抑制剂。 MX69-52 与 MDM2 RING 结构域结合并破坏其与 XIAP IRES，导致 MDM2 和 XIAP 同时抑制，导致癌细胞凋亡。 MX69- 52 的 MTD ≥200 mg/kg，并且在 15 mg/kg 剂量下对白血病异种移植模型有效，这表明 治疗指数。 SEAK Therapeutics 获得了该专利支架的许可，旨在开发最有效的支架 异构体混合物MX69-52中的异构体，即MX69-52d，作为治疗儿科癌症更有效的药物。 SEAK Therapeutics 在此 I 期 SBIR 中建议将 MX69-52d 描述为可行的临床药物并降低其风险 候选人并为此方法提供概念证明。 目标 1. 生成足够量的最有效的旋光异构体 MX69-52d 并确定其 绝对结构。里程碑：（1）生产500毫克MX69-52d（纯度≥98%）； (2) 明确地 确定了 MX69-52d 的绝对结构，以便未来开发立体声特定合成。 目标 2. 确认 MX69-52d 对 MDM2/XIAP 的双重抑制并评估其潜在的脱靶效应 针对一组生理上重要的目标。我们将确认 MX69-52d 保持其模式 作用与其异构体混合物MX69-52相似。我们还将使用以下方法绘制其潜在的脱靶效应 Cerep 的 Safety47 面板。里程碑：(3) 确认 MX69-52d 在两种细胞中均具有双重 MDM2/XIAP 抑制能力 生化和细胞测定； (4) 确定 10 µM 浓度下对重要生理目标的潜在相互作用 （例如 GPCR、离子通道、转运蛋白）以进一步降低 MX69-52d 的风险。 目标 3. 确定 MX69-52d 的最大耐受剂量 (MTD) 和药代动力学 (PK) 参数， 评估其在异种移植模型中的抗癌活性，并评估其对正常人的潜在体内毒性 细胞/组织。我们将使用两只小鼠来评估 MX69-52d 的改善功效和治疗指数 儿童癌症模型。里程碑：（5）MX69-52d的MTD（≥200mg/kg）和PK参数； (6) 已证明在 ≤20 mg/kg 剂量下具有抗癌功效，且无急性毒性。 这项工作的成功将为第二阶段 SBIR 奠定基础，重点是开发 MX69-52d 或 通过 IND 前研究改进类似物，目标是开发一种更有效的治疗儿科癌症的药物。