protein-protein interaction disruptors as therapeutic targets
Post on 03-Feb-2016
36 Views
Preview:
DESCRIPTION
TRANSCRIPT
Protein-protein interaction disruptors as therapeutic targets(an example of a drug discovery
project)
Yvonne Lai, Ph.D.Department of Psychological and Brain Sciences
Indiana University, BloomingtonNavigator, Indiana CTSI (Bloomington campus)
Image from Cayman Chemical
NMDAR Signaling Cascade
Small molecule inhibitors:IC87201/ZL006
NMDAR -----------PSD95----------nNOS-------------NOS1AP--------MAPK------PTSD Depression Stroke
Pain behavior
(CAPON)
Protein-protein interaction disruptors ofNMDAR-dependent signaling
Peptide inhibitorTat-NR2B9c (NA-1)
Target Discovery
Lead Discover
y
Lead Optimizatio
n
Preclinical Evaluation
Full Developmen
tClinical Trials
Assay development
High-throughput screen
Candidate selection
Drug Development
Current collaborative Team
Chemistry:Ganesh Thakur (Northeastern University)-Pushkar Kukarni
Pain efficacy:Andrea Hohmann (IUB)-Wan-hung LeeNeurotoxicity:
Andy Hudmon (IUSM)-Aarti Chawla
PTSD efficacy:Anantha Shekhar (IUSM)-Stephanie Fitz
nNOS-NOS1AP disruptionMichael Courtney (University of Southern Finland)-Lilli Li
Small molecule nNOS-PSD95 protein-protein interaction inhibitors
IC87201:•Inhibited NMDA-induced nNOS-dependent NO formation•Efficacious in chronic pain model (Florio, BJP 2009; Lai, Hohmann unpublished)•Decrease symptoms of PTSD in a rat preclinical model (Shekhar, unpublished) •Efficacious in one depression model (Doucet 2013)
ZL006 (analog of IC87201):•Blocked focal cerebral ischemic damage in mice and rats (Zhou, Nat Med 2010)•Efficacious in one depression model (Doucet 2013)
Additional profile of IC87201/ZL006•Efficacious systemic or i.t., found in CSF and brain tissues•No significant inhibition of 35 target (Receptorgram, MDS Pharma)•No effect on basal pain sensation•No motor ataxia•No effect on novel object recognition•No effect on Morris water maze •No effect on other PDZ P-P interactions (e.g. Erb4-PSD95)
Target Discovery
Lead Discover
y
Assay development
High-throughput screen
HTS (NIH clinical library)
Alpha Screen using NIH clinical library (~800 cpds); nNOS-PSD95 vs nNOS-NOS1AP (Fan, Courtney, Hohmann, Lai, unpublished)
Target Discover
y
Lead Discove
ry
Virtual screen?
Model of PSD95 PDZ2 and the nNOS PDZ complex (PDZ2 is superimposed on the α-syntrophin structure. From Tochio 2000)
Virtual Screen
Seeking collaborators! CTSI CTR deadline May 9!
Preclinical Evaluation
Side effect profile
Drug Development
Additional:•Memory models?•Toxicity profile?•Oral bioavailability?
What are the critical No Go side effects for treatment of pain and PTSD?
Drug DevelopmentCTSI Core Facilities
Target Discover
y
Lead Discove
ry
HTS: Chemical GenomicsIUB-Light Microscopy Imaging Center (high content screen)
Lead Optimization
Need for library:For unusual targets (e.g. P-P interactions)For cell based or more complicated assays
Chemical design and synthesis
Computational modelingVirtual screening
Preclinical Evaluation
Full Development
FundingCTSI Core facility grant (collaboration with Purdue’s BAL)IURCG collaborative grant (Hohmann, IUB and Hudmon, IUSM)
NIH likes our innovative approaches:•Funded:
o R21/NIDA (pain efficacy)-Hohmann PI; Lai, Co-PI•Expected to be funded:
o R21/NIMH (PTSD)-Shekhar, PI; Lai, Co-PIo SBIR phase I (two years)-Lai, PI
What other funding resources? VC, Angel funds?Collaboration with industry?
Collaboration between start ups with academic universities:What is the model? How to optimize expertise and minimize duplications?
top related