Structural basis of γ-secretase inhibition and modulation by small molecule drugs

The innate immunity protein IFITM3 modulates γ-secretase in Alzheimer’s disease

(2020) Ji-Yeun Hur et al.   NATURE

Recognition of the amyloid precursor protein by human γ-secretase

(2019) Rui Zhou et al.   SCIENCE

Uncovering the Binding Mode of γ -Secretase Inhibitors

(2019) Manuel Hitzenberger et al.   ACS Chemical Neuroscience

TREM2 Acts Downstream of CD33 in Modulating Microglial Pathology in Alzheimer’s Disease

(2019) Ana Griciuc et al.   NEURON

Structural basis of Notch recognition by human γ-secretase

(2018) Guanghui Yang et al.   NATURE

Activation of γ-Secretase Trimming Activity by Topological Changes of Transmembrane Domain 1 of Presenilin 1

(2017) Tetsuo Cai et al.   JOURNAL OF NEUROSCIENCE

MotionCor2: anisotropic correction of beam-induced motion for improved cryo-electron microscopy

(2017) Shawn Q Zheng et al.   NATURE METHODS

Semagacestat Is a Pseudo-Inhibitor of γ-Secretase

(2017) Shinji Tagami et al.   Cell Reports

The amyloid hypothesis of Alzheimer's disease at 25 years

(2016) Dennis J Selkoe et al.   EMBO Molecular Medicine

Gamma Secretase Modulators: New Alzheimer’s Drugs on the Horizon?

(2016) Matthew G. Bursavich et al.   JOURNAL OF MEDICINAL CHEMISTRY

Gctf: Real-time CTF determination and correction

(2016) Kai Zhang   JOURNAL OF STRUCTURAL BIOLOGY

Accelerated cryo-EM structure determination with parallelisation using GPUs in RELION-2

(2016) Dari Kimanius et al.   eLife

Notch signaling: An emerging therapeutic target for cancer treatment

(2015) Xun Yuan et al.   CANCER LETTERS

A phase II study of single-agent RO4929097, a gamma-secretase inhibitor of Notch signaling, in patients with recurrent platinum-resistant epithelial ovarian cancer: A study of the Princess Margaret, Chicago and California phase II consortia

(2015) Ivan Diaz-Padilla et al.   GYNECOLOGIC ONCOLOGY

An atomic structure of human γ-secretase

(2015) Xiao-chen Bai et al.   NATURE

Nicastrin functions to sterically hinder γ-secretase–substrate interactions driven by substrate transmembrane domain

(2015) David M. Bolduc et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Peripheral and central effects of γ-secretase inhibition by semagacestat in Alzheimer’s disease

(2015) Rachelle S Doody et al.   Alzheimers Research & Therapy

Measuring the optimal exposure for single particle cryo-EM using a 2.6 Å reconstruction of rotavirus VP6

(2015) Timothy Grant et al.   eLife

Sampling the conformational space of the catalytic subunit of human γ-secretase

(2015) Xiao-chen Bai et al.   eLife

Targeting Prodromal Alzheimer Disease With Avagacestat

(2015) Vladimir Coric et al.   JAMA Neurology

A critique of the drug discovery and phase 3 clinical programs targeting the amyloid hypothesis for Alzheimer disease

(2014) Eric Karran et al.   ANNALS OF NEUROLOGY

Soluble γ-Secretase Modulators Selectively Inhibit the Production of the 42-Amino Acid Amyloid β Peptide Variant and Augment the Production of Multiple Carboxy-Truncated Amyloid β Species

(2014) Steven L. Wagner et al.   BIOCHEMISTRY

Lessons from a Failed γ-Secretase Alzheimer Trial

(2014) Bart De Strooper   CELL

Three-dimensional structure of human γ-secretase

(2014) Peilong Lu et al.   NATURE

Effect of Potent γ-Secretase Modulator in Human Neurons Derived From Multiple Presenilin 1–Induced Pluripotent Stem Cell Mutant Carriers

(2014) Qing Liu et al.   JAMA Neurology

Development and Mechanism of γ-Secretase Modulators for Alzheimer’s Disease

(2013) Christina J. Crump et al.   BIOCHEMISTRY

γ-Secretase Modulator (GSM) Photoaffinity Probes Reveal Distinct Allosteric Binding Sites on Presenilin

(2013) Nikolay Pozdnyakov et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

A Phase 3 Trial of Semagacestat for Treatment of Alzheimer's Disease

(2013) Rachelle S. Doody et al.   NEW ENGLAND JOURNAL OF MEDICINE

Structural Interactions between Inhibitor and Substrate Docking Sites Give Insight into Mechanisms of Human PS1 Complexes

(2013) Yi Li et al.   STRUCTURE

High-resolution noise substitution to measure overfitting and validate resolution in 3D structure determination by single particle electron cryomicroscopy

(2013) Shaoxia Chen et al.   ULTRAMICROSCOPY

Substrate ectodomain is critical for substrate preference and inhibition of γ-secretase

(2013) Satoru Funamoto et al.   Nature Communications

Safety and Tolerability of the γ-Secretase Inhibitor Avagacestat in a Phase 2 Study of Mild to Moderate Alzheimer Disease

(2012) Vladimir Coric et al.   ARCHIVES OF NEUROLOGY

BMS-708,163 Targets Presenilin and Lacks Notch-Sparing Activity

(2012) Christina J. Crump et al.   BIOCHEMISTRY

The mechanism of γ-Secretase dysfunction in familial Alzheimer disease

(2012) Lucía Chávez-Gutiérrez et al.   EMBO JOURNAL

Familial Alzheimer Disease Presenilin-1 Mutations Alter the Active Site Conformation of γ-secretase

(2012) De-Ming Chau et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

Phase I Pharmacologic and Pharmacodynamic Study of the Gamma Secretase (Notch) Inhibitor MK-0752 in Adult Patients With Advanced Solid Tumors

(2012) Ian Krop et al.   JOURNAL OF CLINICAL ONCOLOGY

Phase I Study of RO4929097, a Gamma Secretase Inhibitor of Notch Signaling, in Patients With Refractory Metastatic or Locally Advanced Solid Tumors

(2012) Anthony W. Tolcher et al.   JOURNAL OF CLINICAL ONCOLOGY

A Bayesian View on Cryo-EM Structure Determination

(2011) Sjors H.W. Scheres   JOURNAL OF MOLECULAR BIOLOGY

γ-Secretase inhibitors and modulators for Alzheimer’s disease

(2011) Michael S. Wolfe   JOURNAL OF NEUROCHEMISTRY

The Mutational Landscape of Head and Neck Squamous Cell Carcinoma

(2011) N. Stransky et al.   SCIENCE

PHENIX: a comprehensive Python-based system for macromolecular structure solution

(2010) Paul D. Adams et al.   ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY

Evaluation of Selective  -Secretase Inhibitor PF-03084014 for Its Antitumor Efficacy and Gastrointestinal Safety to Guide Optimal Clinical Trial Design

(2010) P. Wei et al.   MOLECULAR CANCER THERAPEUTICS

An APP inhibitory domain containing the Flemish mutation residue modulates γ-secretase activity for Aβ production

(2010) Yuan Tian et al.   NATURE STRUCTURAL & MOLECULAR BIOLOGY

Modulation of γ-Secretase Reduces β-Amyloid Deposition in a Transgenic Mouse Model of Alzheimer's Disease

(2010) Maria Z. Kounnas et al.   NEURON

Discovery and Evaluation of BMS-708163, a Potent, Selective and Orally Bioavailable γ-Secretase Inhibitor

(2010) Kevin W. Gillman et al.   ACS Medicinal Chemistry Letters

MolProbity: all-atom structure validation for macromolecular crystallography

(2009) Vincent B. Chen et al.   ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY

A γ-secretase inhibitor decreases amyloid-β production in the central nervous system

(2009) Randall J. Bateman et al.   ANNALS OF NEUROLOGY

Targeting Aβ and tau in Alzheimer's disease, an early interim report

(2009) Todd E. Golde et al.   EXPERIMENTAL NEUROLOGY

Development of semagacestat (LY450139), a functional γ-secretase inhibitor, for the treatment of Alzheimer's disease

(2009) David B Henley et al.   EXPERT OPINION ON PHARMACOTHERAPY

 -Secretase: Successive Tripeptide and Tetrapeptide Release from the Transmembrane Domain of  -Carboxyl Terminal Fragment

(2009) M. Takami et al.   JOURNAL OF NEUROSCIENCE

Substrate specificity of γ-secretase and other intramembrane proteases

(2008) A. J. Beel et al.   CELLULAR AND MOLECULAR LIFE SCIENCES

γ-Secretase Inhibition and Modulation for Alzheimers Disease

(2008) Michael Wolfe   Current Alzheimer Research

Discovery of Begacestat, a Notch-1-Sparing γ-Secretase Inhibitor for the Treatment of Alzheimer’s Disease

(2008) Scott C. Mayer et al.   JOURNAL OF MEDICINAL CHEMISTRY

The C-Terminal PAL Motif and Transmembrane Domain 9 of Presenilin 1 Are Involved in the Formation of the Catalytic Pore of the  -Secretase

(2008) C. Sato et al.   JOURNAL OF NEUROSCIENCE