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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要三阴性乳腺癌（TNBC）是最具侵袭性的乳腺癌亚型。约占15% 迄今为止，所有乳腺癌均导致 30% 的乳腺癌死亡。 TNBC 主要采用常规治疗化疗；然而，对治疗的耐药性很常见，导致死亡率很高。重要的是，当前用于耐药 TNBC 的治疗策略的益处；即免疫疗法和抗体- 药物缀合物仅适用于一小部分患者，并且生存获益有限。因此，有迫切需要确定新颖有效的治疗策略来克服化疗耐药性。最近，我们发现缺氧诱导的 ECM 重塑因子赖氨酰氧化酶 (LOX) 是缺氧诱导的 ECM 重塑的关键介质。 TNBC 中的化学耐药性（Saatci 等人，Nature Communications，2020）。我们证明了 LOX 是在化疗耐药肿瘤中过度表达，其抑制作用使最具侵袭性的乳腺肿瘤重新变得敏感使用几种临床相关的小鼠模型对阿霉素进行研究。然而，可用的 LOX 抑制剂有要么是非选择性的，要么是有毒性的。因此，我们这个项目的主要目标是开发有效的、具体的和耐受性良好的 LOX 抑制剂可克服 TNBC 的化疗耐药性，具有较高的转化潜力。通过高通量化合物库筛选和先导化合物转化研究，我们确定了具有有效的 LOX 靶向细胞参与作用的化合物，具有良好的口服药代动力学 (PK) 和具有化学增敏作用，无重大毒性（US PTO 17/693,371 和 PCT/US2022/20086，专利待办的）。从我们目前未优化的先导分子开始，我们的目标是开发具有提高效力、安全性和药物相似度。为了实现这一目标，在快速通道 STTR 的第一阶段授予，我们将通过广泛的结构活性关系生成多样化的小分子库使用我们最初的药效团进行（SAR）研究。我们将测试合成的抑制剂的程度 LOX 酶活性抑制、LOX 结合和对 LOX 的选择性。我们将执行脱靶使用 CEREP 筛选和激酶组分析评估抑制剂。入围候选人将使用细胞系和类器官在 ECM 交联和 3D 化学增敏测定中进一步进行测试。功效、选择性和稳定性更好的抑制剂将进入二期临床。在第二阶段，我们将进行一些 ADME 检测，包括代谢稳定性/特性、Caco-2 渗透性和转运、心脏毒性和基因毒性、血浆蛋白结合、CYP 抑制/诱导/反应表型以改善药物样作用特性，同时保持 TNBC 细胞的靶向效力。详细的 PK/PD 和毒性分析最有希望的候选者将随后使用两者测试其化学增敏剂效果最先进的免疫缺陷（细胞系和患者来源的异种移植物）和免疫功能正常（同基因）小鼠模型。拟议项目的成功完成将带来有效和具体的、铅优化的 LOX 抑制剂可克服 TNBC（最致命的乳腺癌形式）的化疗耐药性。