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Novel selective calpain 1 inhibitors as potential therapeutics in Alzheimer’s disease


Year of Publication:
Contact PI Name:
Ottavio Arancio
Contact PI Affiliation:
Department of Pathology and Cell Biology, The Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University, New York, New York, USA
Mauro Fa, Hong Zhang, Agnieszka Staniszewski, Faisal Saeed, Li W. Shen, Isaac T. Schiefer, Marton I. Siklos, Subhasish Tapadar, Vladislav A. Litosh, Jenny Libien, Pavel A. Petukhov, Andrew F. Teich, Gregory R.J. Thatcher
Primary Reference (PubMED ID):
Funding Source:
National Institute on Aging (NIA)
Study Goal and Principal Findings:

 In previous studies the authors validated the inhibition of calpains as a therapeutic target against their overactivation in AD toward the recovery of synaptic dysfunctions induced by Aβ. These findings led to an effort aimed to discovering novel calpain inhibitors that might be utilized against AD. Here the authors report findings from a phenotypic screening of three generations of peptidomimetic epoxide warhead containing molecules that have been previously proved to be unreactive toward reaction with free thiols while displaying irreversible active site calpain 1 inhibition with sub-micromolar potency.  The investigators designed their drug screening for calpain inhibitors using a phenotypical modality combined with medicinal chemistry refined through target-based computational approach, focusing on the capability of our candidate molecules to protect from the detrimental effect of oligomerized Aβ42 on hippocampal long-term potentiation (LTP), a type of synaptic plasticity thought to underlie learning and memory. Following this screening, the last generation of leads was further tested for pharmacokinetic and toxicological features, and then for the recovery of cognitive impairments in a mouse model of amyloid deposition, the AβPP/PS1 mouse. Data from both functional and preliminary toxicological investigations proved the efficacy, potency, and safety of the novel and selective calpain inhibitors NYC438 and NYC488 as possible therapeutics against Alzheimer's disease.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
Therapeutic Target:
Calpain 1
Therapy Type:
Small Molecule
Therapeutic Agent:
Therapeutic Target:
Calpain 1
Therapy Type:
Small Molecule
Therapeutic Agent:
Therapeutic Target:
Calpain 1
Therapy Type:
Small Molecule
Therapeutic Agent:
Therapeutic Target:
Calpain 1

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:
Not Reported
Animal Model Notes:
APPxPS1 mice for this study were generated by crossing Tg2576 mice ( and PS1(M146V) mice (

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest


Outcome Measured
Outcome Parameters
Contextual Fear Conditioning
Radial Arm Water Maze
Brain-beta Amyloid Peptide 40
Brain-beta Amyloid Peptide 42
Long Term Potentiation (LTP)
field Excitatory Postsynaptic Potential (fEPSP)
Drug Concentration-Brain
Drug Concentration-Plasma
Body Weight
General Behavior
Water Consumption
Tissue Histopathological Profile
Maximum Tolerated Dose (MTD)
Target Engagement (Inhibition Spectrin Cleavage)