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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.

摘要