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:
- 金额:$ 65.47万
- 依托单位:
- 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:
- 关键词:Active SitesAcuteAdvanced DevelopmentAffectAffinityAmericanAntineoplastic AgentsApoptosisBindingBiochemicalCancer EtiologyCell membraneCellsClinicalClinical ResearchClinical TrialsColon CarcinomaCombined Modality TherapyComplexDataDevelopmentDiseaseDrug CombinationsDrug Delivery SystemsDrug KineticsDrug TargetingEvaluationFocal Adhesion Kinase 1Focal AdhesionsFormulationFundingGrowthHealth Care CostsHourHumanImmune Cell SuppressionImmunotherapyIncidenceInvadedLeadLiposomesMalignant NeoplasmsMalignant neoplasm of ovaryMalignant neoplasm of pancreasMelanoma CellMetabolicMetastatic MelanomaModelingNeoplasm MetastasisOncogenicPatient-Focused OutcomesPatientsPeptidesPermeabilityPharmaceutical ChemistryPharmaceutical PreparationsPharmacologyPhasePhosphotransferasesPreparationPrognosisProliferatingPropertyProtein Tyrosine KinaseRattusRegulationResistanceRoleSafetySamplingScaffolding ProteinSeriesSkin CancerSmall Business Technology Transfer ResearchSolid NeoplasmSolubilitySurvival RateToxic effectToxicologyTreatment ProtocolsTumor BurdenWorkalpha helixangiogenesisanimal efficacyanti-CTLA4anti-PD-1anti-canceraqueouscandidate identificationclinical candidateefficacy evaluationefficacy studyhigh riskimprovedimproved outcomein vitro Assayin vivoinhibitorintravenous injectionkinase inhibitorlead optimizationliposomal formulationmalignant breast neoplasmmanufacturemelanomametermigrationmouse modelmutantmyristoylationnanoparticlenoveloverexpressionpatient derived xenograft modelpatient populationpaxillinpre-Investigational New Drug meetingpre-clinicalscaffoldscreeningstapled peptidesuccesstargeted treatmenttherapeutic targettherapy developmenttreatment 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
项目成果
期刊论文数量(0)
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Timothy A Marlowe其他文献
Timothy A Marlowe的其他文献
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{{ truncateString('Timothy A Marlowe', 18)}}的其他基金
Discovery of PPI inhibitors for the FAK FAT domain
发现 FAK FAT 结构域的 PPI 抑制剂
- 批准号:
10576504 - 财政年份:2022
- 资助金额:
$ 65.47万 - 项目类别:
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:
10326066 - 财政年份:2019
- 资助金额:
$ 65.47万 - 项目类别:
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 - 财政年份:2019
- 资助金额:
$ 65.47万 - 项目类别:
Focal Adhesion Kinase - Tumor Biology and Therapeutics
粘着斑激酶 - 肿瘤生物学和治疗学
- 批准号:
10366214 - 财政年份:1996
- 资助金额:
$ 65.47万 - 项目类别:
Focal Adhesion Kinase - Tumor Biology and Therapeutics
粘着斑激酶 - 肿瘤生物学和治疗学
- 批准号:
10561676 - 财政年份:1996
- 资助金额:
$ 65.47万 - 项目类别:
Focal Adhesion Kinase - Tumor Biology and Therapeutics
粘着斑激酶 - 肿瘤生物学和治疗学
- 批准号:
9761994 - 财政年份:1996
- 资助金额:
$ 65.47万 - 项目类别:
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