Development of Non-Catalytic Peptide Inhibitors of Focal Adhesion Kinase (FAK) for Use in Melanoma

开发用于治疗黑色素瘤的粘着斑激酶 (FAK) 非催化肽抑制剂

基本信息

批准号：
10670300
负责人：
Timothy A Marlowe
金额：
$ 65.47万
依托单位：
FAKNOSTICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10670300
关键词：
Active Sites Acute Advanced Development Affect Affinity American Antineoplastic Agents Apoptosis Binding Biochemical Cancer Etiology Cell membrane Cells Clinical Clinical Research Clinical Trials Colon Carcinoma Combined Modality Therapy Complex Data Development Disease Drug Combinations Drug Delivery Systems Drug Kinetics Drug Targeting Evaluation Focal Adhesion Kinase 1 Focal Adhesions Formulation Funding Growth Health Care Costs Hour Human Immune Cell Suppression Immunotherapy Incidence Invaded Lead Liposomes Malignant Neoplasms Malignant neoplasm of ovary Malignant neoplasm of pancreas Melanoma Cell Metabolic Metastatic Melanoma Modeling Neoplasm Metastasis Oncogenic Patient-Focused Outcomes Patients Peptides Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Phase Phosphotransferases Preparation Prognosis Proliferating Property Protein Tyrosine Kinase Rattus Regulation Resistance Role Safety Sampling Scaffolding Protein Series Skin Cancer Small Business Technology Transfer Research Solid Neoplasm Solubility Survival Rate Toxic effect Toxicology Treatment Protocols Tumor Burden Work alpha helix angiogenesis animal efficacy anti-CTLA4 anti-PD-1 anti-cancer aqueous candidate identification clinical candidate efficacy evaluation efficacy study high risk improved improved outcome in vitro Assay in vivo inhibitor intravenous injection kinase inhibitor lead optimization liposomal formulation malignant breast neoplasm manufacture melanoma meter migration mouse model mutant myristoylation nanoparticle novel overexpression patient derived xenograft model patient population paxillin pre-Investigational New Drug meeting pre-clinical scaffold screening stapled peptide success targeted treatment therapeutic target therapy development treatment strategy

项目摘要

Abstract Melanoma is the deadliest form of skin cancer, affecting an estimated 1.2 million Americans. The disease has a high propensity for dissemination, and metastatic melanoma has a dismal prognosis, with a median survival of only 5–8 months. Healthcare costs for melanoma in 2021 are projected to reach nearly $4 billion, with a rising incidence rate. Despite considerable efforts in recent years to develop more effective targeted and immunotherapies against melanoma, the 5-year survival rate for stage IV melanoma patients remains around 20%. Thus, there is a significant unmet clinical need for novel treatment strategies to improve outcomes for patients with melanoma. Focal Adhesion Kinase (FAK) is a non-receptor tyrosine kinase and scaffolding protein considered to be a highly promising cancer drug target due to its involvement in multiple hallmarks of cancer, including migration, invasion, metastasis, apoptosis, proliferation, angiogenesis, and immune-cell suppression. FAK is overexpressed in 60–80% of multiple solid tumors, including breast, colon, ovarian, and pancreatic cancer, and is massively upregulated in human melanoma samples. Despite its potential as a therapeutic target, the FAK inhibitors developed to date only target the ATP-binding pocket of the kinase domain and have shown little clinical success. However, recent proof-of-principle studies have shown that the focal adhesion targeting (FAT) scaffolding domain of FAK is an essential regulator of melanoma survival, growth, and metastasis. Additionally, FAKnostics has preliminary data showing that FAT domain inhibition selectively decreases viability of NRAS-mutant melanoma cells, a subset of melanoma that represents 20-30% of all cases and has no effective targeted therapies. On the basis of these findings, FAKnostics has identified a first-in-class series of peptidic FAK inhibitors that directly target the FAT domain of FAK and have significant anti-cancer effects in NRAS- mutant melanoma. In Phase I, FAKnostics identified a stapled peptide candidate with ~5,000-fold higher binding affinity to the FAK FAT domain versus the native paxillin LD2 motif. Furthermore, we have demonstrated proof- of-concept of this approach by confirming in vivo efficacy in a syngeneic mouse model. Through this Phase II project, FAKnostics seeks to continue the development of this treatment approach through the following specific aims: 1) Optimize lead peptides through iterations of medicinal chemistry to improve cellular potency and drug- like properties; 2) Evaluate top optimized peptides in pharmacokinetic and in vivo efficacy studies to select preclinical candidate peptide; 3) Complete formulation studies of final clinical candidate peptide and evaluate safety/toxicology in rats; and 4) Determine patient population suitable for clinical trials using melanoma patient- derived xenograft and syngeneic efficacy modelsand determine optimal combinational treatment regimen. Upon successful completion of these aims, FAKnostics intends to initiate GMP manufacturing and GLP safety/toxicology studies in preparation for an FDA IND application and a clinical trial.

抽象的黑色素瘤是皮肤癌最致命的形式，影响了约120万美国人。该病有传播的高倾向和转移性黑色素瘤的预后很糟糕，中位生存期的中位数只有5-8个月。黑色素瘤在2021年的医疗保健费用预计将达到近40亿美元，随着事件率。尽管近年来努力为建立更有效的针对性和针对黑色素瘤的免疫疗法，IV期黑色素瘤患者的5年生存率仍在 20％。这是对新的治疗策略的重大未满足的临床需求，以改善结果黑色素瘤患者。焦点粘附激酶（FAK）是一种非受体酪氨酸激酶和脚手架蛋白由于它参与了多种癌症标志，因此被认为是癌症药物较高的癌症靶标包括迁移，侵袭，转移，凋亡，增殖，血管生成和免疫细胞抑制。 FAK在60-80％的多种实体瘤中过表达，包括乳房，结肠，卵巢和胰腺癌症，并在人黑色素瘤样品中大规模更新。尽管具有治疗靶标的潜力迄今为止，FAK抑制剂仅针对激酶域的ATP结合口袋，并显示了很少的临床成功。但是，最近的原理证明研究表明，焦点粘合剂的靶向（脂肪）FAK的脚手架结构域是黑色素瘤生存，生长和转移的重要调节剂。此外，Faknostics具有初步数据，表明脂肪结构域抑制选择性降低生存能力 NRAS突变的黑色素瘤细胞，这是一个代表所有病例的20-30％的黑色素瘤的子集，没有有效靶向疗法。根据这些发现，Faknostics已经确定了一类肽 FAK抑制剂直接靶向FAK的脂肪结构域，并在Nras-中具有显着的抗癌作用突变黑色素瘤。在第一阶段，Faknostics确定了一个分阶段的候选肽，具有约5,000倍的结合与天然Paxillin LD2基序相对于FAK脂肪结构域的亲和力。此外，我们已经证明了证明通过确认合成小鼠模型中体内效率的概念概念。通过这个阶段II 项目，Faknostics试图通过以下特定目的：1）通过迭代医学化学的迭代来优化铅的宠物，以提高细胞效力和药物 - 喜欢属性； 2）评估药代动力学和体内效率研究中的最佳优化肽以选择临床前候选肽； 3）最终临床候选肽的完整公式研究并评估大鼠的安全/毒理学； 4）确定适用于使用黑色素瘤患者的临床试验的患者人群 - 衍生的定义和合成效率模型，并确定最佳组合治疗方案。之上这些目标成功完成，Faknostics打算启动GMP制造和GLP 安全/毒理学研究为FDA IND应用和临床试验做准备。