Novel ubiquitin protease inhibitor for treating asthma
Novel ubiquitin protease inhibitor for treating asthma
批准号:
9200067
负责人:
Kumar Suresh
金额:
$20.59万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-07-06 至 2018-06-30
关键词:
Adrenal Cortex HormonesAdverse effectsAffectAgonistAmericanAnimal ModelAsthmaBiological AssayCell Differentiation processCellsChronicComplexDevelopmentDigit structureDiseaseDisease modelDown-RegulationDrug DesignEconomic BurdenEnzymesFamilyGoalsHumanImmuneImmune System DiseasesImmune responseImmune systemImmunityImpairmentInflammationInflammatoryInflammatory ResponseInterleukin-17Interleukin-4Interleukin-5IrrigationLeadLiquid substanceLungLung InflammationMessenger RNAMusMutationPathogenesisPathologyPathway interactionsPatientsPharmaceutical PreparationsPhasePlayProductionProtease InhibitorProteinsPublic HealthQuality of lifeRecruitment ActivityRegulatory T-LymphocyteResearch PersonnelRheumatic Heart DiseaseRoleSerumSocietiesSputumSteroid ResistanceSteroid-resistant asthmaSymptomsSystemT-LymphocyteTestingTherapeuticUbiquitinairway hyperresponsivenessairway remodelingasthmaticasthmatic patientbasecell typecounterscreencytokineenzyme pathwayeosinophilhigh throughput screeningimprovedin vitro Modelinhibitor/antagonistinnovationloss of functionmembermimeticsmouse modelmulticatalytic endopeptidase complexneurotensin mimic 1neutrophilnovelperipheral bloodpreclinical evaluationpreclinical studyresponsescreeningsmall moleculesmall molecule inhibitorsmall molecule librariestargeted treatmenttranscription factorubiquitin-protein ligase
中文摘要
哮喘是影响全世界3亿人的主要公共卫生问题。虽然没有治愈方法,
英文摘要
Asthma is a major public health problem affecting 300 million people worldwide. While no cure is available,
symptoms can be managed with corticosteroids and β2-agonists, which can exert deleterious side effects.
Improved, targeted therapies are needed for steroid-resistant and other forms of asthma. A complex disease,
asthma entails chronic inflammation, hyper-reactivity, and remodeling of the airways, and immunity driven by
TH2 and TH17 cells contributes to the pathogenesis of asthma subtypes. Cytokines secreted by these immune
cells act to recruit eosinophils and neutrophils, leading to the pathology of asthma; further, crosstalk between
TH2 and TH17 responses ultimately leads to further amplification and elevation of inflammation. Targeted
suppression of TH2 and TH17 differentiation and/or responses is the general approach taken here for treating
the underlying drivers of asthma. In particular, the ubiquitin pathway regulates immune responses, and ubiquitin-
based drugs may have utility in controlling asthma. For example, the E3 ligase Itch suppresses both TH2 and
TH17 differentiation and cytokine production upon activation by Nedd4-family interacting protein 1 (Ndfip1).
Progenra has identified small molecule Ndfip1 mimetics which are able to activate Itch, impairing IL-4 production
and promoting Treg rather than TH2 cell differentiation. Recently, USP4, a deubiquitylase, has been shown to be
critical for TH17 differentiation by stabilizing TH17 specific transcription factor RORgammaT, and pharmacological
inhibition of USP4 blocks TH17 differentiation. Thus, one can selectively target TH17 and TH2 differentiation by
modulating USP4 function. It is therefore proposed here to discover and develop selective small molecule
inhibitors of USP4; these are expected to limit TH17 differentiation, dampening inflammatory asthmatic
responses. In addition, USP4 inhibitors will be combined with Progenra's small molecule Ndfip1 mimetics (Itch
activators) to selectively impair TH17 and TH2 differentiation. To accomplish this therapeutic goal, high throughput
screening for USP4 inhibitors will be conducted employing Progenra's screening platform and 220,000 member
small molecule library. Cellular proof of concept assays will be conducted on selected hits to evaluate their effect
on TH17 differentiation and cytokine production in relevant in vitro models. In Phase II, lead optimization and
additional preclinical studies will be performed with selected inhibitors to ascertain their ability to modulate USP4
functions and to dampen inflammation in relevant mouse models. The ultimate commercial goal is the development
of novel small molecule agents that can be used in combination to treat (steroid resistant) asthma.
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海外基金