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

• 批准号: 10468903
• 负责人: Timothy A Marlowe
• 金额: $ 67.08万
• 依托单位: FAKNOSTICS, LLC
• 依托单位国家: 美国
• 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/10468903
• 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; 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; 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; Property; 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; angiogenesis; animal efficacy; anti-CTLA4; anti-PD-1; anti-cancer; aqueous; base; clinical candidate; efficacy evaluation; efficacy study; high risk; improved; improved outcome; in vitro Assay; in vivo; inhibitor; intravenous injection; kinase inhibitor; lead optimization; malignant breast neoplasm; meetings; melanoma; migration; mouse model; mutant; nanoparticle; novel; overexpression; patient derived xenograft model; patient population; paxillin; pre-clinical; scaffold; screening; stapled peptide; success; targeted treatment; therapeutic target; therapy development; treatment strategy

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 黑色素瘤是最致命的皮肤癌，估计影响 120 万美国人。该病有一个 扩散倾向高，转移性黑色素瘤预后较差，中位生存期为 只需5-8个月。 2021 年黑色素瘤的医疗费用预计将达到近 40 亿美元，并且不断上升 发病率。尽管近年来做出了巨大努力来开发更有效的有针对性和 针对黑色素瘤的免疫疗法，IV 期黑色素瘤患者的 5 年生存率仍保持在 20%。因此，对新的治疗策略以改善预后的临床需求存在显着的未满足的需求 黑色素瘤患者。粘着斑激酶 (FAK) 是一种非受体酪氨酸激酶和支架蛋白 由于它涉及癌症的多种特征，被认为是一个非常有前途的癌症药物靶标， 包括迁移、侵袭、转移、细胞凋亡、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，包括乳腺癌、结肠癌、卵巢癌和胰腺癌 癌症，并且在人类黑色素瘤样本中大量上调。尽管它具有作为治疗靶点的潜力， 迄今为止开发的 FAK 抑制剂仅针对激酶结构域的 ATP 结合袋，并已表明 临床成功甚少。然而，最近的原理验证研究表明，粘着斑靶向 FAK 的 (FAT) 支架结构域是黑色素瘤存活、生长和转移的重要调节因子。 此外，FAKnostics 的初步数据表明 FAT 域抑制选择性降低活力 NRAS 突变黑色素瘤细胞是黑色素瘤的一个子集，占所有病例的 20-30%，目前尚无有效的治疗方法 靶向治疗。根据这些发现，FAKnostics 确定了一系列一流的肽 FAK抑制剂直接靶向FAK的FAT结构域，在NRAS中具有显着的抗癌作用- 突变黑色素瘤。在第一阶段，FAKnostics 鉴定出一种结合力高约 5,000 倍的候选钉合肽 FAK FAT 结构域与天然桩蛋白 LD2 基序的亲和力。此外，我们还证明了—— 通过在同基因小鼠模型中确认体内功效来了解该方法的概念。通过这个第二阶段 项目中，FAKnostics 寻求通过以下具体措施继续开发这种治疗方法 目标：1) 通过药物化学的迭代优化先导肽，以提高细胞效力和药物- 喜欢属性； 2) 在药代动力学和体内功效研究中评估最佳优化的肽以选择 临床前候选肽； 3) 完成最终临床候选肽的配方研究并评估 大鼠的安全性/毒理学； 4) 确定适合使用黑色素瘤患者进行临床试验的患者群体 衍生异种移植和同基因疗效模型并确定最佳组合治疗方案。之上 为了成功实现这些目标，FAKnostics 打算启动 GMP 生产和 GLP 为 FDA IND 申请和临床试验做准备的安全/毒理学研究。