Structural Basis of AZD9291 Selectivity for EGFR T790M

Journal of Medicinal Chemistry
Xiao-E YanCai-Hong Yun

Abstract

AZD9291 (Osimertinib) is highly effective in treating EGFR-mutated non-small-cell lung cancers (NSCLCs) with T790M-mediated drug resistance. Despite the remarkable success of AZD9291, its binding pose with EGFR T790M remains unclear. Here, we report unbiased, atomic-level molecular dynamics (MD) simulations in which spontaneous association of AZD9291 with EGFR kinases having WT and T790M mutant gatekeepers was observed. Simulation-generated structural models suggest that the binding pose of AZD9291 with T790M differs from its binding pose with the WT, and that AZD9291 interacts extensively with the gatekeeper residue (Met 790) in T790M but not with Thr 790 in the WT, which explains why AZD9291 binds T790M with higher affinity. The MD simulation-generated models were confirmed by experimentally determined EGFR/T790M complex crystal structures. This work may facilitate the rational design of drugs that can overcome resistance mutations to AZD9291, and more generally it suggests the potential of using unbiased MD simulation to elucidate small-molecule binding poses.

References

Oct 3, 1998·Acta Crystallographica. Section D, Biological Crystallography·A T BrüngerG L Warren
Mar 1, 1985·Physical Review A: General Physics·W G Hoover
Apr 30, 2004·Journal of Computational Chemistry·Junmei WangDavid A Case
Jul 24, 2004·Acta Crystallographica. Section D, Biological Crystallography·Alexander W Schüttelkopf, Daan M F van Aalten
Aug 27, 2004·Proceedings of the National Academy of Sciences of the United States of America·William PaoHarold Varmus
Feb 25, 2005·The New England Journal of Medicine·Susumu KobayashiBalázs Halmos
Jul 21, 2006·Acta Crystallographica. Section D, Biological Crystallography·Wladek MinorMaksymilian Chruszcz
Nov 7, 2006·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Marissa N BalakWilliam Pao
Jan 30, 2008·Proceedings of the National Academy of Sciences of the United States of America·Cai-Hong YunMichael J Eck
Aug 1, 2007·Journal of Applied Crystallography·Airlie J McCoyRandy J Read
Jun 12, 2009·The Journal of Physical Chemistry. B·Robert B Best, Gerhard Hummer
Dec 25, 2009·Nature·Wenjun ZhouPasi A Jänne
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Paul D AdamsPeter H Zwart
Apr 13, 2010·Acta Crystallographica. Section D, Biological Crystallography·P EmsleyK Cowtan
Apr 22, 2010·Proteins·Kresten Lindorff-LarsenDavid E Shaw
May 7, 2011·Journal of the American Chemical Society·Yibing ShanDavid E Shaw
Apr 12, 2013·Proceedings of the National Academy of Sciences of the United States of America·Yibing ShanDavid E Shaw
Nov 5, 2013·The Journal of Chemical Physics·Ross A LippertDavid E Shaw
Dec 19, 2013·Proceedings of the National Academy of Sciences of the United States of America·Phillip A SchwartzBrion William Murray
Apr 30, 2015·The New England Journal of Medicine·Pasi A JänneMalcolm Ranson
Apr 30, 2015·The New England Journal of Medicine·Lecia V SequistD Ross Camidge
May 8, 2015·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Dalia ErcanPasi A Jänne
Nov 3, 2015·Journal of Structural Biology·Yuliana YosaatmadjaChristopher J Squire
Jan 6, 2016·Drugs·Sarah L Greig
Jul 1, 2016·Drugs·Esther S Kim
May 11, 2017·Journal of Chemical Theory and Computation·Robert M ParrishC David Sherrill
Mar 3, 2020·The Journal of Chemical Physics·Cristian PredescuDavid E Shaw

❮ Previous
Next ❯

Citations

May 20, 2021·Protein Science : a Publication of the Protein Society·David E Heppner, Michael J Eck
Jun 1, 2021·Expert Opinion on Drug Discovery·Florian Wittlinger, Stefan A Laufer
Sep 1, 2021·European Journal of Medicinal Chemistry·Francesca FerlenghiMarco Mor

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.

Related Papers

Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer
Oliver GautschiLukas C Heukamp
Lung Cancer : Journal of the International Association for the Study of Lung Cancer
Puey Ling ChiaThomas John
Annals of Oncology : Official Journal of the European Society for Medical Oncology
David PlanchardJ C Soria
Lung Cancer : Journal of the International Association for the Study of Lung Cancer
Audrey ValléeMarc G Denis
© 2021 Meta ULC. All rights reserved