From structure to clinic: Design of a muscarinic M1 receptor agonist with potential to treatment of Alzheimer's disease

Alastair J.H. Brown; Sophie J. Bradley; Fiona H. Marshall; Giles A. Brown; Kirstie A. Bennett; Jason Brown; Julie E. Cansfield; David M. Cross; Chris de Graaf; Brian D. Hudson; Louis Dwomoh; João M. Dias; James C. Errey; Edward Hurrell; Jan Liptrot; Giulio Mattedi; Colin Molloy; Pradeep J. Nathan; Krzysztof Okrasa; Greg Osborne; Jayesh C. Patel; Mark Pickworth; Nathan Robertson; Shahram Shahabi; Christoffer Bundgaard; Keith Phillips; Lisa M. Broad; Anushka V. Goonawardena; Stephen R. Morairty; Michael Browning; Francesca Perini; Gerard R. Dawson; John F.W. Deakin; Robert T. Smith; Patrick M. Sexton; Julie Warneck; Mary Vinson; Tim Tasker; Benjamin G. Tehan; Barry Teobald; Arthur Christopoulos; Christopher J. Langmead; Ali Jazayeri; Robert M. Cooke; Prakash Rucktooa; Miles S. Congreve; Malcolm Weir; Andrew B. Tobin

doi:10.1016/j.cell.2021.11.001

From structure to clinic: Design of a muscarinic M1 receptor agonist with potential to treatment of Alzheimer's disease

Alastair J.H. Brown, Sophie J. Bradley, Fiona H. Marshall, Giles A. Brown, Kirstie A. Bennett, Jason Brown, Julie E. Cansfield, David M. Cross, Chris de Graaf, Brian D. Hudson, Louis Dwomoh, João M. Dias, James C. Errey, Edward Hurrell, Jan Liptrot, Giulio Mattedi, Colin Molloy, Pradeep J. Nathan, Krzysztof Okrasa, Greg OsborneJayesh C. Patel, Mark Pickworth, Nathan Robertson, Shahram Shahabi, Christoffer Bundgaard, Keith Phillips, Lisa M. Broad, Anushka V. Goonawardena, Stephen R. Morairty, Michael Browning, Francesca Perini, Gerard R. Dawson, John F.W. Deakin, Robert T. Smith, Patrick M. Sexton, Julie Warneck, Mary Vinson, Tim Tasker, Benjamin G. Tehan, Barry Teobald, Arthur Christopoulos, Christopher J. Langmead, Ali Jazayeri, Robert M. Cooke, Prakash Rucktooa, Miles S. Congreve, Malcolm Weir, Andrew B. Tobin

Research output: Contribution to journal › Article › Research › peer-review

67 Citations (Scopus)

Abstract

Current therapies for Alzheimer's disease seek to correct for defective cholinergic transmission by preventing the breakdown of acetylcholine through inhibition of acetylcholinesterase, these however have limited clinical efficacy. An alternative approach is to directly activate cholinergic receptors responsible for learning and memory. The M1-muscarinic acetylcholine (M1) receptor is the target of choice but has been hampered by adverse effects. Here we aimed to design the drug properties needed for a well-tolerated M1-agonist with the potential to alleviate cognitive loss by taking a stepwise translational approach from atomic structure, cell/tissue-based assays, evaluation in preclinical species, clinical safety testing, and finally establishing activity in memory centers in humans. Through this approach, we rationally designed the optimal properties, including selectivity and partial agonism, into HTL9936—a potential candidate for the treatment of memory loss in Alzheimer's disease. More broadly, this demonstrates a strategy for targeting difficult GPCR targets from structure to clinic.

Original language	English
Pages (from-to)	5886-5901.e22
Number of pages	38
Journal	Cell
Volume	184
Issue number	24
DOIs	https://doi.org/10.1016/j.cell.2021.11.001
Publication status	Published - 24 Nov 2021

Keywords

Alzheimer's disease
G protein coupled receptors
M1 muscarinic acetylcholine receptor
muscarinic receptor
neurodegeneration
prion disease
structural based drug design

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Brown, A. J. H., Bradley, S. J., Marshall, F. H., Brown, G. A., Bennett, K. A., Brown, J., Cansfield, J. E., Cross, D. M., de Graaf, C., Hudson, B. D., Dwomoh, L., Dias, J. M., Errey, J. C., Hurrell, E., Liptrot, J., Mattedi, G., Molloy, C., Nathan, P. J., Okrasa, K., ... Tobin, A. B. (2021). From structure to clinic: Design of a muscarinic M1 receptor agonist with potential to treatment of Alzheimer's disease. Cell, 184(24), 5886-5901.e22. https://doi.org/10.1016/j.cell.2021.11.001

@article{c52e850272a24f49bb9c92e42a081ac5,

title = "From structure to clinic: Design of a muscarinic M1 receptor agonist with potential to treatment of Alzheimer's disease",

abstract = "Current therapies for Alzheimer's disease seek to correct for defective cholinergic transmission by preventing the breakdown of acetylcholine through inhibition of acetylcholinesterase, these however have limited clinical efficacy. An alternative approach is to directly activate cholinergic receptors responsible for learning and memory. The M1-muscarinic acetylcholine (M1) receptor is the target of choice but has been hampered by adverse effects. Here we aimed to design the drug properties needed for a well-tolerated M1-agonist with the potential to alleviate cognitive loss by taking a stepwise translational approach from atomic structure, cell/tissue-based assays, evaluation in preclinical species, clinical safety testing, and finally establishing activity in memory centers in humans. Through this approach, we rationally designed the optimal properties, including selectivity and partial agonism, into HTL9936—a potential candidate for the treatment of memory loss in Alzheimer's disease. More broadly, this demonstrates a strategy for targeting difficult GPCR targets from structure to clinic.",

keywords = "Alzheimer's disease, G protein coupled receptors, M1 muscarinic acetylcholine receptor, muscarinic receptor, neurodegeneration, prion disease, structural based drug design",

author = "Brown, {Alastair J.H.} and Bradley, {Sophie J.} and Marshall, {Fiona H.} and Brown, {Giles A.} and Bennett, {Kirstie A.} and Jason Brown and Cansfield, {Julie E.} and Cross, {David M.} and {de Graaf}, Chris and Hudson, {Brian D.} and Louis Dwomoh and Dias, {Jo{\~a}o M.} and Errey, {James C.} and Edward Hurrell and Jan Liptrot and Giulio Mattedi and Colin Molloy and Nathan, {Pradeep J.} and Krzysztof Okrasa and Greg Osborne and Patel, {Jayesh C.} and Mark Pickworth and Nathan Robertson and Shahram Shahabi and Christoffer Bundgaard and Keith Phillips and Broad, {Lisa M.} and Goonawardena, {Anushka V.} and Morairty, {Stephen R.} and Michael Browning and Francesca Perini and Dawson, {Gerard R.} and Deakin, {John F.W.} and Smith, {Robert T.} and Sexton, {Patrick M.} and Julie Warneck and Mary Vinson and Tim Tasker and Tehan, {Benjamin G.} and Barry Teobald and Arthur Christopoulos and Langmead, {Christopher J.} and Ali Jazayeri and Cooke, {Robert M.} and Prakash Rucktooa and Congreve, {Miles S.} and Malcolm Weir and Tobin, {Andrew B.}",

note = "Funding Information: We wish to acknowledge Andrew S. Dor? for assistance with analysis of the crystallographic data, Alex Godwood for assistance with analysis of the efficacy data, and Geor Bakker for help with additional analysis of the fMRI and EEG data. This work is partially funded by a University of Glasgow Lord Kelvin Adam Smith Fellowship (S.J.B.); an MRC MICA, MR/P019366/1 (A.B.T. S.J.B.); a Wellcome Trust Collaborative Award, 201529/Z/16/Z (A.B.T. A.C. P.M.S.); SULSA Dementia Seed Funding (A.B.T.). We acknowledge the BSU facilities at the Cancer Research UK Beatson Institute (C596/A17196) and the Biological Services at the University of Glasgow. We also thank Simon Brooke and Helen Sanger for conducting assays on the muscarinic receptor expressing cell lines. A.J.H.B. G.A.B. M.S.C. R.M.C. A.J. C.J.L. F.H.M. T.T. B.G.T. M.W. and A.B.T. devised the program of work. A.B.T. A.J.H.B. and F.H.M. wrote the paper with assistance from all other authors. J.E.C. M.P. M.S.C. and G.A.B. devised and carried out the chemical syntheses. D.M.C. J.L. P.J.N. M.V. J.W. and T.T. developed and oversaw the clinical program. S.J.B. compiled and analyzed data, contributed to writing paper, and conducted prion mouse work and pharmacology. A.C. and P.M.S. contributed to mouse prion work and analysis of structural biology. L.M.B.; ligand synthesis, mouse pharmacokinetic studies. K.P. S.S. and L.M.B.; in vivo electrophysiology. C.B. and D.M.C.; pharmacokinetics. N.R. J.B. J.C.E. and J.C.P. devised and carried out the conformational thermostabilization and mutagenesis of the receptor, characterised expression constructs, and performed radioligand binding analysis of mutants. K.O. established protocols for expression, purification, mass spectrometry QC, and optimised protein concentration for LCP crystallization trials. Computational analysis of the structure and modeling was carried out by B.G.T. and R.T.S. J.F.W.D. and P.R. established the platform/protocols for LCP crystallization and solved the structure. K.A.B. J.B. E.H. and G.O. carried out and analyzed the in vitro pharmacology data. C.d.G. and G.M. conducted molecular dynamic analysis and contributed to structural biology analysis. B.D.H. and L.D. conducted biased ligand experiments. A.V.G. and S.R.M. developed and analyzed NHP EEG data. F.P. M.B. G.R.D. and J.F.W.D. supported development, oversight, and analysis of clinical fMRI study. T.T. and M.W. are shareholders and board members of Sosei Heptares. The authors A.J.H.B. G.A.B. K.A.B. J.B. J.E.C. M.S.C. R.M.C. J.C.E. E.H. A.J. C.J.L. J.L. F.H.M. P.J.N. K.O. G.O. J.C.P. M.P. N.R. P.R. B.G.T. R.T.S. C.d.G. G.M. and B.T. are or have been employees of Heptares Therapeutics and are shareholders of Sosei Heptares. Funding Information: We wish to acknowledge Andrew S. Dor{\'e} for assistance with analysis of the crystallographic data, Alex Godwood for assistance with analysis of the efficacy data, and Geor Bakker for help with additional analysis of the fMRI and EEG data. This work is partially funded by a University of Glasgow Lord Kelvin Adam Smith Fellowship (S.J.B.); an MRC MICA, MR/P019366/1 (A.B.T., S.J.B.,); a Wellcome Trust Collaborative Award, 201529/Z/16/Z (A.B.T., A.C., P.M.S.); SULSA Dementia Seed Funding (A.B.T.). We acknowledge the BSU facilities at the Cancer Research UK Beatson Institute ( C596/A17196 ) and the Biological Services at the University of Glasgow. We also thank Simon Brooke and Helen Sanger for conducting assays on the muscarinic receptor expressing cell lines. Publisher Copyright: {\textcopyright} 2021",

year = "2021",

month = nov,

day = "24",

doi = "10.1016/j.cell.2021.11.001",

language = "English",

volume = "184",

pages = "5886--5901.e22",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "24",

}

Brown, AJH, Bradley, SJ, Marshall, FH, Brown, GA, Bennett, KA, Brown, J, Cansfield, JE, Cross, DM, de Graaf, C, Hudson, BD, Dwomoh, L, Dias, JM, Errey, JC, Hurrell, E, Liptrot, J, Mattedi, G, Molloy, C, Nathan, PJ, Okrasa, K, Osborne, G, Patel, JC, Pickworth, M, Robertson, N, Shahabi, S, Bundgaard, C, Phillips, K, Broad, LM, Goonawardena, AV, Morairty, SR, Browning, M, Perini, F, Dawson, GR, Deakin, JFW, Smith, RT, Sexton, PM, Warneck, J, Vinson, M, Tasker, T, Tehan, BG, Teobald, B, Christopoulos, A , Langmead, CJ, Jazayeri, A, Cooke, RM, Rucktooa, P, Congreve, MS, Weir, M & Tobin, AB 2021, 'From structure to clinic: Design of a muscarinic M1 receptor agonist with potential to treatment of Alzheimer's disease', Cell, vol. 184, no. 24, pp. 5886-5901.e22. https://doi.org/10.1016/j.cell.2021.11.001

TY - JOUR

T1 - From structure to clinic

T2 - Design of a muscarinic M1 receptor agonist with potential to treatment of Alzheimer's disease

AU - Brown, Alastair J.H.

AU - Bradley, Sophie J.

AU - Marshall, Fiona H.

AU - Brown, Giles A.

AU - Bennett, Kirstie A.

AU - Brown, Jason

AU - Cansfield, Julie E.

AU - Cross, David M.

AU - de Graaf, Chris

AU - Hudson, Brian D.

AU - Dwomoh, Louis

AU - Dias, João M.

AU - Errey, James C.

AU - Hurrell, Edward

AU - Liptrot, Jan

AU - Mattedi, Giulio

AU - Molloy, Colin

AU - Nathan, Pradeep J.

AU - Okrasa, Krzysztof

AU - Osborne, Greg

AU - Patel, Jayesh C.

AU - Pickworth, Mark

AU - Robertson, Nathan

AU - Shahabi, Shahram

AU - Bundgaard, Christoffer

AU - Phillips, Keith

AU - Broad, Lisa M.

AU - Goonawardena, Anushka V.

AU - Morairty, Stephen R.

AU - Browning, Michael

AU - Perini, Francesca

AU - Dawson, Gerard R.

AU - Deakin, John F.W.

AU - Smith, Robert T.

AU - Sexton, Patrick M.

AU - Warneck, Julie

AU - Vinson, Mary

AU - Tasker, Tim

AU - Tehan, Benjamin G.

AU - Teobald, Barry

AU - Christopoulos, Arthur

AU - Langmead, Christopher J.

AU - Jazayeri, Ali

AU - Cooke, Robert M.

AU - Rucktooa, Prakash

AU - Congreve, Miles S.

AU - Weir, Malcolm

AU - Tobin, Andrew B.

N1 - Funding Information: We wish to acknowledge Andrew S. Dor? for assistance with analysis of the crystallographic data, Alex Godwood for assistance with analysis of the efficacy data, and Geor Bakker for help with additional analysis of the fMRI and EEG data. This work is partially funded by a University of Glasgow Lord Kelvin Adam Smith Fellowship (S.J.B.); an MRC MICA, MR/P019366/1 (A.B.T. S.J.B.); a Wellcome Trust Collaborative Award, 201529/Z/16/Z (A.B.T. A.C. P.M.S.); SULSA Dementia Seed Funding (A.B.T.). We acknowledge the BSU facilities at the Cancer Research UK Beatson Institute (C596/A17196) and the Biological Services at the University of Glasgow. We also thank Simon Brooke and Helen Sanger for conducting assays on the muscarinic receptor expressing cell lines. A.J.H.B. G.A.B. M.S.C. R.M.C. A.J. C.J.L. F.H.M. T.T. B.G.T. M.W. and A.B.T. devised the program of work. A.B.T. A.J.H.B. and F.H.M. wrote the paper with assistance from all other authors. J.E.C. M.P. M.S.C. and G.A.B. devised and carried out the chemical syntheses. D.M.C. J.L. P.J.N. M.V. J.W. and T.T. developed and oversaw the clinical program. S.J.B. compiled and analyzed data, contributed to writing paper, and conducted prion mouse work and pharmacology. A.C. and P.M.S. contributed to mouse prion work and analysis of structural biology. L.M.B.; ligand synthesis, mouse pharmacokinetic studies. K.P. S.S. and L.M.B.; in vivo electrophysiology. C.B. and D.M.C.; pharmacokinetics. N.R. J.B. J.C.E. and J.C.P. devised and carried out the conformational thermostabilization and mutagenesis of the receptor, characterised expression constructs, and performed radioligand binding analysis of mutants. K.O. established protocols for expression, purification, mass spectrometry QC, and optimised protein concentration for LCP crystallization trials. Computational analysis of the structure and modeling was carried out by B.G.T. and R.T.S. J.F.W.D. and P.R. established the platform/protocols for LCP crystallization and solved the structure. K.A.B. J.B. E.H. and G.O. carried out and analyzed the in vitro pharmacology data. C.d.G. and G.M. conducted molecular dynamic analysis and contributed to structural biology analysis. B.D.H. and L.D. conducted biased ligand experiments. A.V.G. and S.R.M. developed and analyzed NHP EEG data. F.P. M.B. G.R.D. and J.F.W.D. supported development, oversight, and analysis of clinical fMRI study. T.T. and M.W. are shareholders and board members of Sosei Heptares. The authors A.J.H.B. G.A.B. K.A.B. J.B. J.E.C. M.S.C. R.M.C. J.C.E. E.H. A.J. C.J.L. J.L. F.H.M. P.J.N. K.O. G.O. J.C.P. M.P. N.R. P.R. B.G.T. R.T.S. C.d.G. G.M. and B.T. are or have been employees of Heptares Therapeutics and are shareholders of Sosei Heptares. Funding Information: We wish to acknowledge Andrew S. Doré for assistance with analysis of the crystallographic data, Alex Godwood for assistance with analysis of the efficacy data, and Geor Bakker for help with additional analysis of the fMRI and EEG data. This work is partially funded by a University of Glasgow Lord Kelvin Adam Smith Fellowship (S.J.B.); an MRC MICA, MR/P019366/1 (A.B.T., S.J.B.,); a Wellcome Trust Collaborative Award, 201529/Z/16/Z (A.B.T., A.C., P.M.S.); SULSA Dementia Seed Funding (A.B.T.). We acknowledge the BSU facilities at the Cancer Research UK Beatson Institute ( C596/A17196 ) and the Biological Services at the University of Glasgow. We also thank Simon Brooke and Helen Sanger for conducting assays on the muscarinic receptor expressing cell lines. Publisher Copyright: © 2021

PY - 2021/11/24

Y1 - 2021/11/24

N2 - Current therapies for Alzheimer's disease seek to correct for defective cholinergic transmission by preventing the breakdown of acetylcholine through inhibition of acetylcholinesterase, these however have limited clinical efficacy. An alternative approach is to directly activate cholinergic receptors responsible for learning and memory. The M1-muscarinic acetylcholine (M1) receptor is the target of choice but has been hampered by adverse effects. Here we aimed to design the drug properties needed for a well-tolerated M1-agonist with the potential to alleviate cognitive loss by taking a stepwise translational approach from atomic structure, cell/tissue-based assays, evaluation in preclinical species, clinical safety testing, and finally establishing activity in memory centers in humans. Through this approach, we rationally designed the optimal properties, including selectivity and partial agonism, into HTL9936—a potential candidate for the treatment of memory loss in Alzheimer's disease. More broadly, this demonstrates a strategy for targeting difficult GPCR targets from structure to clinic.

AB - Current therapies for Alzheimer's disease seek to correct for defective cholinergic transmission by preventing the breakdown of acetylcholine through inhibition of acetylcholinesterase, these however have limited clinical efficacy. An alternative approach is to directly activate cholinergic receptors responsible for learning and memory. The M1-muscarinic acetylcholine (M1) receptor is the target of choice but has been hampered by adverse effects. Here we aimed to design the drug properties needed for a well-tolerated M1-agonist with the potential to alleviate cognitive loss by taking a stepwise translational approach from atomic structure, cell/tissue-based assays, evaluation in preclinical species, clinical safety testing, and finally establishing activity in memory centers in humans. Through this approach, we rationally designed the optimal properties, including selectivity and partial agonism, into HTL9936—a potential candidate for the treatment of memory loss in Alzheimer's disease. More broadly, this demonstrates a strategy for targeting difficult GPCR targets from structure to clinic.

KW - Alzheimer's disease

KW - G protein coupled receptors

KW - M1 muscarinic acetylcholine receptor

KW - muscarinic receptor

KW - neurodegeneration

KW - prion disease

KW - structural based drug design

UR - http://www.scopus.com/inward/record.url?scp=85119605873&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2021.11.001

DO - 10.1016/j.cell.2021.11.001

M3 - Article

C2 - 34822784

AN - SCOPUS:85119605873

SN - 0092-8674

VL - 184

SP - 5886-5901.e22

JO - Cell

JF - Cell

IS - 24

ER -

From structure to clinic: Design of a muscarinic M1 receptor agonist with potential to treatment of Alzheimer's disease

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