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Development of Spleen Tyrosine Kinase (SYK) negative allosteric modifiers for therapeutic intervention in Alzheimer's disease.

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R42AG062063-01
Agency Tracking Number: R42AG062063
Amount: $224,920.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: NIA
Solicitation Number: PAS18-188
Timeline
Solicitation Year: 2018
Award Year: 2018
Award Start Date (Proposal Award Date): 2018-09-30
Award End Date (Contract End Date): 2019-08-31
Small Business Information
2040 WHITFIELD AVE
Sarasota, FL 34243-3922
United States
DUNS: 948616235
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 MICHAEL MULLAN
 (941) 752-2949
 mmullan@archerpharma.com
Business Contact
 LAUREN HORNE
Phone: (941) 752-2949
Email: lhorne@roskampinstitute.org
Research Institution
 ROSKAMP INSTITUTE, INC.
 
2040 WHITFIELD AVE
SARASOTA, FL 34243-3922
United States

 Domestic Nonprofit Research Organization
Abstract

Pathological hallmarks of Alzheimerandapos s diseaseADinclude extracellular deposits of Apeptidesintraneuronal
aggregates of abnormally phosphorylated tau protein and neuroinflammationMost proposed AD disease
modifying therapies have focused on strategies that reduce brain Aamyloid or tau pathological accumulationHoweversuch approaches have been unsuccessful in late stage AD clinical trials and may only be most
useful as prophylacticsleaving millions of AD patients without therapeutic optionsThere is therefore a critical
need to evaluate therapeutic targets downstream of Aamyloid and tau pathologiesWe have determined that
the spleen tyrosine kinaseSYKis pathologically activated in neurons and microglia both in AD patients and in
AD preclinical mouse modelsand colocalizes with AD pathological hallmarkssuggesting SYK is a
downstream target of Aand tau pathologiesWe have identified that nilvadipinea known antihypertensive
dihydropyridineDHPthat improves cognition and reduces the development of AD pathological hallmarks
including neuroinflammation in AD preclinical modelsmediates its AD effects via an allosteric inhibition of SYK
highlighting SYK as a therapeutic target for ADWe have recently concluded a large randomizeddoubleblindplacebo controlled phase III trial of nilvadipine in mild to moderate AD revealing that nilvadipine has
cognitive benefits for mildparticularly very mildAD in whom it slows the rate of cognitive declineThe main
goal of these studies is the development of a selective SYK negative allosteric modulatorNAMmore potent
than nilvadipinefor the treatment of AD without the blood pressure lowering effectsAs the orthosteric site
configuration is conserved among kinaseswhich can lead to a lower specificity of a drugresulting in adverse
side effectswe elected a drug discovery strategy exploiting SYK allosteric sites to lead to more selective
therapeutic agentsIn this Fast Track STTR applicationPhase I will allow the identification of a suitable SYK
NAM scaffold for drug development and the establishment of computational models to orient the rational
design and synthesis of novel SYK NAMsPhase II will improve the SYK inhibitory activity and optimize the
ADMEAbsorptionDistributionMetabolismand Excretionproperties of the SYK NAM scaffolds to identify an
advanced SYK NAM scaffold leadThe efficacy of the lead SYK NAM will be ultimately explored in preclinical
models of AD exhibiting Atau and inflammatory pathologiesGiven our previous preclinical data obtained
with nilvadipine and another selective SYK inhibitorBAYwe anticipate that targeting SYK with a
SYK NAM should alleviate some of the downstream consequences of Aand tau accumulation including
neuroinflammationsynaptic loss and neurodegenerationand should also reduce the propagation of the tau
pathology and Aamyloid accumulationThe SYK NAM scaffolds that we are developing have the potential to
simultaneously affect neuroinflammatory processesAamyloid and tau pathologies and may lead to more
effective AD treatments than targeting a single pathological aspect of the disease Alzheimerandapos s diseaseADis an ever increasing health concern among the aging
population and is the most common form of dementia affecting nearlymillion
individuals worldwidewith no effective disease modifying therapies and many clinical
failures of therapeutics focused solely on amyloid or tau pathologiesDrugs with multi modal action are an alternative strategy to treat the diseaseand our
lead compoundnilvadipineis a demonstrably safe small molecule dihydropyridineDHPwith anti amyloidanti tau and anti inflammatory characteristicswhich has
recently demonstrated efficacy in an exploratory subset of very mild AD patients from
our Phase III trialNilvadipineandapos s anti Alzheimer activity is through inhibition of the spleen tyrosine kinaseSYKand in this proposal we will develop and screen negative allosteric SYK
modulatorsbased on DHP and related scaffoldswith greater potencyspecificity and
preclinical efficacyto advance to AD clinical trials

* Information listed above is at the time of submission. *

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