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Protein-protein interaction disruptors as therapeutic targets

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, Bloomington Navigator, Indiana CTSI (Bloomington campus). NMDAR Signaling Cascade.

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Protein-protein interaction disruptors as therapeutic targets

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  1. 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, Bloomington Navigator, Indiana CTSI (Bloomington campus)

  2. NMDAR Signaling Cascade Image from Cayman Chemical

  3. Protein-protein interaction disruptors of NMDAR-dependent signaling Tat-NR2B9c (NA-1) Peptide inhibitor Pain behavior (CAPON) Small molecule inhibitors: IC87201/ZL006 NMDAR-----------PSD95----------nNOS-------------NOS1AP--------MAPK------PTSD Depression Stroke

  4. Drug Development Target Discovery Lead Discovery Lead Optimization Clinical Trials Preclinical Evaluation Full Development Assay development Candidate selection High-throughput screen

  5. Current collaborative Team Pain efficacy: Andrea Hohmann (IUB)-Wan-hung Lee Neurotoxicity: Andy Hudmon (IUSM)-Aarti Chawla • Chemistry: • Ganesh Thakur (Northeastern University)-PushkarKukarni PTSD efficacy: Anantha Shekhar (IUSM)-Stephanie Fitz nNOS-NOS1AP disruption Michael Courtney (University of Southern Finland)-Lilli Li

  6. 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Inhibited NMDA-induced nNOS-dependent NO formation • Efficacious in chronic pain model (Florio, BJP 2009; Lai, Hohmann unpublished) • Decrease symptoms of PTSD in a rat preclinical model (Shekhar, unpublished) • Efficacious in one depression model (Doucet2013) • ZL006 (analog of IC87201): • Blocked focal cerebral ischemic damage in mice and rats (Zhou, Nat Med 2010) • Efficacious in one depression model (Doucet2013)

  7. 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)

  8. HTS (NIH clinical library) Target Discovery Lead Discovery Assay development High-throughput screen Alpha Screen using NIH clinical library (~800 cpds); nNOS-PSD95 vs nNOS-NOS1AP (Fan, Courtney, Hohmann, Lai, unpublished)

  9. Virtual screen? Seeking collaborators! CTSI CTR deadline May 9! Target Discovery Lead Discovery Virtual Screen Model of PSD95 PDZ2 and the nNOS PDZ complex (PDZ2 is superimposed on the α-syntrophin structure. From Tochio 2000)

  10. Drug Development What are the critical No Go side effects for treatment of pain and PTSD? Preclinical Evaluation Side effect profile • Additional: • Memory models? • Toxicity profile? • Oral bioavailability?

  11. Drug Development CTSI Core Facilities Lead Optimization Full Development Preclinical Evaluation Target Discovery Lead Discovery Need for library: For unusual targets (e.g. P-P interactions) For cell based or more complicated assays HTS: Chemical Genomics IUB-Light Microscopy Imaging Center (high content screen) Computational modeling Virtual screening Chemical design and synthesis

  12. Funding • CTSI Core facility grant (collaboration with Purdue’s BAL) • IURCG collaborative grant (Hohmann, IUB and Hudmon, IUSM) • NIH likes our innovative approaches: • Funded: • R21/NIDA (pain efficacy)-Hohmann PI; Lai, Co-PI • Expected to be funded: • R21/NIMH (PTSD)-Shekhar, PI; Lai, Co-PI • 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?

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