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: 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
• 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

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.

摘要 黑色素瘤是最致命的皮肤癌，估计有120万美国人受到影响。这种疾病有一种 转移的黑色素瘤有很高的扩散倾向，预后很差，中位生存期为 只有5-8个月。预计2021年黑色素瘤的医疗费用将达到近40亿美元，而且还会上升 发病率。尽管近年来做出了相当大的努力来制定更有效、更有针对性的和 针对黑色素瘤的免疫疗法，IV期黑色素瘤患者的5年存活率仍然存在 20%因此，有一个重要的未得到满足的临床需求，需要新的治疗策略来改善预后。 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 被认为是非常有希望的抗癌药物靶点，因为它参与了癌症的多种特征， 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%的多发性实体瘤中过度表达，包括乳腺、结肠、卵巢和胰腺。 癌症，并在人类黑色素瘤样本中大量上调。尽管它有成为治疗靶点的潜力， 到目前为止，开发的FAK抑制剂仅针对激酶结构域的ATP结合口袋，并已显示 在临床上几乎没有成功。然而，最近的原则证明研究表明，焦点黏附靶向 FAK的(脂肪)支架结构域是黑色素瘤生存、生长和转移的重要调节因子。 此外，FAKnostics的初步数据显示，脂肪结构域抑制选择性地降低了生存能力 在NRAS突变的黑色素瘤细胞中，占所有病例的20%-30%的黑色素瘤的一个亚群，没有有效 有针对性的治疗。根据这些发现，FAKnostics已经确定了一系列一流的多肽 直接靶向FAK脂肪结构域并在NRAS中具有显著抗癌作用的FAK抑制剂- 突变黑色素瘤。在第一阶段，FAKnostics发现了一种结合能力高约5000倍的装订多肽候选 与FAK脂肪结构域的亲和力与天然paxlin LD2基序的亲和力。此外，我们已经证明了- OF-通过在同基因小鼠模型中确认体内疗效来确定该方法的概念。通过此阶段II 项目，FAKnostics寻求通过以下具体措施继续发展这种治疗方法 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- 2)在药代动力学和体内药效研究中评价最优的多肽，以选择 临床前候选多肽；3)完成最终临床候选多肽的配方研究和评价 老鼠的安全性/毒理学；以及4)确定适合使用黑色素瘤患者进行临床试验的患者群体- 衍生的异种移植和同种异体疗效模型，并确定最佳联合治疗方案。vt.在.的基础上 成功完成这些目标，FAKnostics打算启动GMP制造和GLP 安全性/毒理学研究正在为FDA IND申请和临床试验做准备。