Steven Wagner, Ph.D.

Principal Investigator, Department of Neurosciences, School of Medicine, University of California, San Diego

Dr. Wagner joined the Department of Neurosciences in the School of Medicine at the University of California, San Diego in June of 2009.  Prior to that Dr. Wagner co-founded TorreyPines Therapeutics, then named Neurogenetics, in 2000 serving as its Chief Scientific Officer for nine years.  Previously, Dr. Wagner was the Director of Protein Biochemistry at SIBIA Neurosciences from 1991-1999.  He served as the program head of SIBIA’s Alzheimer’s disease drug discovery collaboration with Bristol-Myers Squibb (BMS). This collaboration resulted in the first gamma-secretase inhibitor for Alzheimer’s disease to reach the clinic.  Dr. Wagner was a member of SIBIA’s Strategic Planning and Drug Discovery Steering Committees and a member of the Joint Steering Committee between SIBIA and BMS.  Dr. Wagner is an inventor on numerous patents and patent applications and has published over 50 chapters and research papers in the top scientific journals.  Prior to leading SIBIA’s Alzheimer’s disease drug discovery efforts, Dr. Wagner was a Research Associate Professor in the Department of Microbiology and Molecular Genetics at the University of California at Irvine where he co-authored the initial purification and identification of the human amyloid precursor protein (APP).  Dr. Wagner received his B.S. in chemistry from Bellarmine College and received his M.S. and Ph.D. in biochemistry from the Health Sciences Center at the University of Louisville School of Medicine.

Funded Research

Project Description Researchers Funding
Binding Site Characterization of a Novel Pyridazine-Derived Class of γ-Secretase Modulators

This research will identify the critical sites of interaction between novel pyridazine-derived soluble gamma secretase modulators (SGSMs) and their molecular target, as well as provide valuable information toward fostering an improved understanding of the mechanism by which these therapeutically relevant small molecules affect the production of specific Abeta peptide variants without inhibiting the enzyme’s activity. Despite the development of numerous potent SGSMs, the precise molecular target and the mechanism of action of this clinically relevant pyridazine series remain unknown.

Acceleration of FDA-Required GLP Gene Toxicity Studies with the GSM BPN-15606

As a result of an Ames positive result in a single salmonella strain (T98), the FDA is requiring that, prior to our pre-IND meeting with them, we perform a GLP Ames assay with a form of BPN-15606 (besylate salt form) that is equivalent to what will be used in our IND-enabling toxicity studies and Phase 1 clinical trials. In addition, the FDA recommended that we perform two additional in vivo gene toxicity assays in rodents: the Micronucleus assay and the Comet assay.

Lead Optimization and Lead Evolution of Potent SGSMs for the Treatment of Alzheimer’s Disease

This application outlines a highly focused extension of an NIH-funded Blueprint Neurotherapeutics (BPN) U01 program to create more potent, soluble, brain penetrant, nontoxic small molecules known as soluble gamma-secretase modulators (SGSMs) that act to enhance the activity/processivity of y-secretase, thereby reducing the levels of Aβ42 and to a lesser extent Aβ40 while increasing the levels of shorter Abeta peptides (e.g., Aβ38 and Aβ37)

Elucidation of the Molecular Target of Potent γ-Secretase Modulators

A promising series of soluble γ-secretase modulators (SGSMs) has been discovered in our lab at UCSD in collaboration with MGH which inhibit the formation of the aggregation prone Aβ42 peptide in favor of shorter less pathogenic Aβ isoforms. Despite the development of numerous potent SGSMs, the molecular target and the mechanism of action remain unknown. We propose the synthesis of three distinct clickable SGSM-photoprobes for cross-linking studies to demonstrate the binding site of these ligands within the γ-secretase enzyme.

Elucidation of the mechanism of action of Gamma Secretase Modulators

This project focuses on ultimately defining the structure of a soluble gamma-secretase modulator (SGSM)-bound gamma-secretase enzyme complex at high resolution.

Novel Soluble Gamma-Secretase Modulators for the Treatment of Alzheimer’s Disease Identification of the Molecular Target of Potent Gamma-Secretase Modulators

The goal of this project is to identify a series of highly potent gamma-secretase modulators able to lower Abeta42 and Abeta40 production while concomitantly increasing the less toxic production of Abeta38 without measurably affecting gamma-secretase-mediated processing of the Notch 1 receptor (which is very important in a variety of cellular processes for cell-to-cell communication).

2011 to 2012

Novel Soluable Gamma-Secretase Modulators

Building on in vitro characterization of a novel series of soluable gamma-secretase modulators (SGSMs) funded by Cure Alzheimer’s Fund, the current project is a thorough pharmacological or in vivo examination of these molecules to identify the best or “lead” drug candidate.

Design, Synthesis and Characterization of Novel and Potent Gamma Secretase Modulators: Physiochemical and Pharmacokinetic Properties

During the past year, our laboratory at UCSD (Wagner laboratory), in close collaboration with the Tanzi laboratory at MGH, discovered, synthesized and characterized (in vitro) a novel series of molecules able to potently prevent the formation of what is currently thought to be the pathogenic culprit of Alzheimer’s disease (AD).


Selected Publications

These published papers resulted from Cure Alzheimer’s Fund support.
Steven L. Wagner, Kevin D. Rynearson, Steven K. Duddy, Can Zhang, Phuong D. Nguyen, Ann Becker, Uyen Vo, Deborah Masliah, Louise Monte, Justin B. Klee, Corinne M. Echmalian, Weiming Xia, Luisa Quinti, Graham Johnson, Jiunn H. Lin, Doo Y. Kim, William C. Mobley, Robert A. Rissman, Rudolph E. Tanzi, Pharmacological and Toxicological Properties of the Potent Oral gamma-Secretase Modulator BPN-15606, Journal Of Pharmacology And Experimental Therapeutics, 362(1), Jul 2017, 31-44
Carla D’Avanzo, Christopher Sliwinski, Steven L. Wagner, Rudolph E. Tanzi, Doo Yeon Kim, and Dora M. Kovacs, γ-Secretase modulators reduce endogenous amyloid β42 levels in human neural progenitor cells without altering neuronal differentiation, The FASEB Journal, 29(8), 22 April 2015, 3335-3341
Wagner SL, Tanzi RE, Mobley WC, Galasko D, Potential Use of γ-Secretase Modulators in the Treatment of Alzheimer Disease, Arch Neurol., July 16, 2012
Kim M, Suh J, Romano D, Truong MH, Mullin K, Hooli B, Norton D, Tesco G, Elliot K, Wagner SL, Moir RD, Becker KD, Tanzi RE., Potential late-onset Alzheimer's disease-associated mutations in the ADAM10 gene attenuate alpha-secretase activity., Human Molecular Genetics, Vol 18, Oct 15, 2009
Bertram L, Lange CL, Mullin K, Parkinson M, Hsiao M, Hogan MF,  Schjeide BMM, Hooli B, DeVito J, Ionita I, Jiang H, Laird N, Moscarillo T, Ohlsen KL, Elliott K, Wang X, Hu-Lince D, Ryder M, Murphy A, Wagner SL, Blacker D, Becker KD, Tanzi RE., Genome-wide Association Analysis Reveals Putative Alzheimer's Disease Susceptibility Loci in Addition to APOE, Am. J. Hum. Genet., 83, November 2008, 623-632