Developing novel LOX inhibitors to target chemotherapy resistant TNBC

开发新型 LOX 抑制剂以靶向化疗耐药的 TNBC

• 批准号: 10696810
• 负责人: Ozgur Sahin
• 金额: $ 40.65万
• 依托单位: LOXIGEN, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-08 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10696810
• 关键词: 3-Dimensional; Address; Antibody-drug conjugates; Benchmarking; Binding; Binding Proteins; Biological Assay; Biological Availability; Biometry; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Patient; Breast Cancer cell line; Cancer Biology; Canis familiaris; Cardiotoxicity; Cell Line; Cells; Cessation of life; Chemoresistance; Chemosensitization; Collagen; Communication; Complement; Dedications; Doxorubicin; Drug Kinetics; Extracellular Matrix; Fibronectins; Goals; Grant; Hypoxia; Immunocompetent; Immunologic Deficiency Syndromes; Immunotherapy; In Vitro; Induction of Apoptosis; Lead; Legal patent; Libraries; Mammary Neoplasms; Maximum Tolerated Dose; Mediator; Medical Oncology; Metabolic; Mission; Modeling; Modification; Monoamine Oxidase; Mus; Nature; Oral; Organoids; Outcome; PTK2 gene; Patients; Penetration; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phenotype; Phosphotransferases; Plasma Proteins; Property; Protein-Lysine 6-Oxidase; Public Health; Reaction; Resistance; Safety; Serum Proteins; Signal Transduction; Small Business Technology Transfer Research; Solubility; Specificity; Structure-Activity Relationship; Testing; Therapeutic; Time; Toxic effect; United States National Institutes of Health; aggressive breast cancer; breast surgery; cancer subtypes; cellular targeting; chemosensitizing agent; chemotherapy; clinically relevant; crosslink; design; disability; drug candidate; drug discovery; effective therapy; genotoxicity; improved; in vitro Assay; in vivo; inhibitor; lead optimization; mRNA Expression; malignant breast neoplasm; member; meter; mortality; mouse model; novel; overexpression; patient derived xenograft model; pharmacokinetics and pharmacodynamics; pharmacophore; protein expression; screening; small molecule libraries; success; synergism; therapy resistant; translational potential; treatment strategy; triple-negative invasive breast carcinoma; tumor

PROJECT SUMMARY Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype. It accounts for ~15% of all breast cancer yet is responsible for 30% of breast cancer deaths. TNBC is treated primarily by conventional chemotherapy; however, resistance to therapy is common, leading to high mortality rates. Importantly, the benefit of current therapeutic strategies used in chemoresistant TNBC; i.e., immunotherapy and antibody- drug conjugates, is confined to only a fraction of patients, and survival benefit is limited. Therefore, there is an urgent need to identify novel and effective treatment strategies to overcome resistance to chemotherapy. Recently, we identified hypoxia-induced ECM re-modeler, lysyl oxidase (LOX) as a key mediator of chemoresistance in TNBC (Saatci et al, Nature Communications, 2020). We showed that LOX is overexpressed in chemoresistant tumors, and its inhibition re-sensitizes the most aggressive breast tumors to doxorubicin using several clinically-relevant mouse models. However, the available LOX inhibitors are either non-selective or has toxicity. Hence, our main objective in this project is to develop potent, specific and well-tolerated LOX inhibitors to overcome chemoresistance in TNBC that has a high translational potential. Through high-throughput compound library screening and hit-to-lead conversion studies, we identified compounds with potent on-target cellular engagement of LOX, with good oral pharmacokinetics (PK) and with chemosensitizer effect without major toxicity (US PTO 17/693,371 and PCT/US2022/20086, patent pending). Starting from our current non-optimized lead molecule, we aim to develop lead compounds with increased potency, safety and drug-likeness. To accomplish this goal, in Phase I of this Fast-Track STTR grant, we will generate a diverse library of small molecules via an extensive structure activity relationship (SAR) study using our initial pharmacophore. We will test the synthesized inhibitors with respect to the degree of LOX enzymatic activity inhibition, LOX binding and selectivity towards LOX. We will perform the off-target assessment of the inhibitors using CEREP screen as well as kinome profiling. The shortlisted candidates will further be tested in ECM crosslinking and 3D chemosensitization assays using both cell lines and organoids. Inhibitors with better efficacy, selectivity and stability will move to Phase II. In Phase II, we will perform several ADME assays, including metabolic stability/identity, Caco-2 permeability and transport, cardiotoxicity and genotoxicity, plasma protein binding, CYP inhibition/induction/reaction phenotyping to improve drug-like properties while maintaining on-target potency in TNBC cells. Detailed PK/PD and toxicity analyses of the most promising candidates will be carried out followed by testing their chemosensitizer effect using both state-of-the-art immunodeficient (cell line- and patient-derived xenografts) and immunocompetent (syngeneic) mice models. The successful completion of the proposed project will lead to potent and specific, lead-optimized LOX inhibitors to overcome chemoresistance in TNBC, the deadliest form of breast cancer.

项目摘要 三重阴性乳腺癌（TNBC）是最具侵略性的乳腺癌亚型。它占约15％ 所有乳腺癌却造成30％的乳腺癌死亡。 TNBC主要通过常规治疗 化学疗法；但是，对治疗的抵抗力很常见，导致高死亡率。重要的是， 化学耐药性TNBC使用的当前治疗策略的益处；即免疫疗法和抗体 - 药物共轭物仅限于一小部分患者，生存益处受到限制。因此，有 迫切需要确定新颖有效的治疗策略，以克服对化学疗法的抵抗力。 最近，我们确定缺氧诱导的ECM重模型，赖氨酸氧化酶（LOX）作为关键介体 TNBC中的化学抗性（Saatci等人，自然通讯，2020年）。我们表明Lox是 过表达化学抗性肿瘤，其抑制作用重新敏感了最具侵略性的乳腺肿瘤 使用多种临床上的小鼠模型来进行阿霉素。但是，可用的LOX抑制剂是 非选择性或毒性。因此，该项目的主要目标是发展有效，具体和 耐受耐受性的LOX抑制剂，以克服具有高转化潜力的TNBC化学耐药性。 通过高通量复合库筛选和命中率转换研究，我们确定了 LOX的有效靶向细胞参与，具有良好的口服药代动力学（PK）和 具有无重大毒性的化学敏化效果（美国PTO 17/693,371和PCT/US2022/20086，专利 待办的）。从当前的非优化铅分子开始，我们旨在与 提高效力，安全性和吸毒性。为了实现这一目标，在这个快速轨道的I阶段 Grant，我们将通过广泛的结构活动关系生成一个小分子的多元化库 （SAR）使用我们的初始药理研究。我们将根据程度测试合成的抑制剂 Lox酶活性抑制，对LOX的结合和对LOX的选择性的抑制作用。我们将执行脱离目标 使用小脑屏幕和kinome分析评估抑制剂。入围的候选人将 进一步在ECM交联和3D化学敏化测定中使用两种细胞系和类器官进行测试。 具有更好功效，选择性和稳定性的抑制剂将转移到II期。在第二阶段，我们将执行几个 ADME分析，包括代谢稳定性/身份，CACO-2渗透性和运输，心脏毒性和 遗传毒性，血浆蛋白结合，CYP抑制/诱导/反应表型，以改善药物样 在维持TNBC细胞中靶向效力的同时。详细的PK/PD和毒性分析 最有希望的候选人将进行，然后使用两者都测试其化学敏化效果 最先进的免疫缺陷（细胞系和患者衍生的异种移植物）和免疫能力 （合成）小鼠模型。拟议项目的成功完成将导致有效的，具体， 铅优化的LOX抑制剂克服TNBC的化学耐药性，TNBC是最致命的乳腺癌形式。