Design and development of lysyl tRNA synthetase inhibitors, for the treatment of tuberculosis

Susan H. Davis; Michael Mathieson; Kirsteen I. Buchanan; Alice Dawson; Alasdair Smith; Mattia Cocco; Fabio K. Tamaki; John M. Post; Beatriz Baragaña; Chimed Jansen; Michael Kiczun; Fabio Zuccotto; Gavin Wood; Paul Scullion; Peter C. Ray; Ola Epemolu; Eva Maria Lopez-Román; Laura Guijarro López; Curtis A. Engelhart; Jia Kim; Paula A. Pino; Dirk Schnappinger; Kevin D. Read; Lourdes Encinas; Robert H. Bates; Paul G. Wyatt; Simon R. Green; Laura A. T. Cleghorn

doi:10.1021/acs.jmedchem.5c01331

Design and development of lysyl tRNA synthetase inhibitors, for the treatment of tuberculosis

Susan H. Davis, Michael Mathieson, Kirsteen I. Buchanan, Alice Dawson, Alasdair Smith, Mattia Cocco, Fabio K. Tamaki, John M. Post, Beatriz Baragaña, Chimed Jansen, Michael Kiczun, Fabio Zuccotto, Gavin Wood, Paul Scullion, Peter C. Ray, Ola Epemolu, Eva Maria Lopez-Román, Laura Guijarro López, Curtis A. Engelhart, Jia KimPaula A. Pino, Dirk Schnappinger, Kevin D. Read, Lourdes Encinas, Robert H. Bates, Paul G. Wyatt, Simon R. Green, Laura A. T. Cleghorn (Lead / Corresponding author)

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Abstract

There is currently a public health crisis due to the rise of multidrug-resistant tuberculosis cases, as well as the rise in the number of deaths from tuberculosis. To achieve the United Nations Sustainable Development Goal of ending the tuberculosis epidemic by 2030, new treatments are urgently required. We previously reported the discovery of 49, a preclinical candidate that acted through inhibition of the Mycobacterium tuberculosis lysyl tRNA synthetase (LysRS). In this report, the full medicinal chemistry program is reviewed from the original hit through to the optimized lead. The work was guided by the first crystal structures of M. tuberculosis LysRS. The physicochemical and pharmacokinetic properties were optimized to afford compounds suitable for evaluation in mouse efficacy models of tuberculosis and with the potential for clinical development.

Original language	English
Pages (from-to)	16459-16482
Number of pages	24
Journal	Journal of Medicinal Chemistry
Volume	68
Issue number	15
Early online date	1 Aug 2025
DOIs	https://doi.org/10.1021/acs.jmedchem.5c01331
Publication status	Published - 14 Aug 2025

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1021/acs.jmedchem.5c01331Licence: CC BY

Final published versionFinal published version, 5.6 MBLicence: CC BY

A Centre of Excellence for Lead Optimisation for Diseases of the Developing World (Joint funding by Wellcome & Gates)
Gilbert, I. (Investigator), Gray, D. (Investigator), Read, K. (Investigator) & Wyatt, P. (Investigator)
1/07/13 → 31/10/18
Project: Research
State-of-the-Art Facilities for Structural Biology at the University of Dundee
Hunter, B. (Investigator), Lilley, D. (Investigator), Owen-Hughes, T. (Investigator), Wyatt, P. (Investigator) & van Aalten, D. (Investigator)
1/03/12 → 28/02/17
Project: Research

X-Ray Crystallography
Centre for Advanced Scientific Technologies
Facility/equipment: Facility

Cite this

Davis, S. H., Mathieson, M., Buchanan, K. I., Dawson, A., Smith, A., Cocco, M., Tamaki, F. K., Post, J. M., Baragaña, B., Jansen, C., Kiczun, M., Zuccotto, F., Wood, G., Scullion, P., Ray, P. C., Epemolu, O., Lopez-Román, E. M., Guijarro López, L., Engelhart, C. A., ... Cleghorn, L. A. T. (2025). Design and development of lysyl tRNA synthetase inhibitors, for the treatment of tuberculosis. Journal of Medicinal Chemistry, 68(15), 16459-16482. https://doi.org/10.1021/acs.jmedchem.5c01331

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title = "Design and development of lysyl tRNA synthetase inhibitors, for the treatment of tuberculosis",

abstract = "There is currently a public health crisis due to the rise of multidrug-resistant tuberculosis cases, as well as the rise in the number of deaths from tuberculosis. To achieve the United Nations Sustainable Development Goal of ending the tuberculosis epidemic by 2030, new treatments are urgently required. We previously reported the discovery of 49, a preclinical candidate that acted through inhibition of the Mycobacterium tuberculosis lysyl tRNA synthetase (LysRS). In this report, the full medicinal chemistry program is reviewed from the original hit through to the optimized lead. The work was guided by the first crystal structures of M. tuberculosis LysRS. The physicochemical and pharmacokinetic properties were optimized to afford compounds suitable for evaluation in mouse efficacy models of tuberculosis and with the potential for clinical development.",

author = "Davis, \{Susan H.\} and Michael Mathieson and Buchanan, \{Kirsteen I.\} and Alice Dawson and Alasdair Smith and Mattia Cocco and Tamaki, \{Fabio K.\} and Post, \{John M.\} and Beatriz Baraga{\~n}a and Chimed Jansen and Michael Kiczun and Fabio Zuccotto and Gavin Wood and Paul Scullion and Ray, \{Peter C.\} and Ola Epemolu and Lopez-Rom{\'a}n, \{Eva Maria\} and \{Guijarro L{\'o}pez\}, Laura and Engelhart, \{Curtis A.\} and Jia Kim and Pino, \{Paula A.\} and Dirk Schnappinger and Read, \{Kevin D.\} and Lourdes Encinas and Bates, \{Robert H.\} and Wyatt, \{Paul G.\} and Green, \{Simon R.\} and Cleghorn, \{Laura A. T.\}",

year = "2025",

month = aug,

day = "14",

doi = "10.1021/acs.jmedchem.5c01331",

language = "English",

volume = "68",

pages = "16459--16482",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "15",

}

Davis, SH, Mathieson, M, Buchanan, KI, Dawson, A, Smith, A, Cocco, M, Tamaki, FK, Post, JM, Baragaña, B, Jansen, C, Kiczun, M, Zuccotto, F, Wood, G, Scullion, P, Ray, PC, Epemolu, O, Lopez-Román, EM, Guijarro López, L, Engelhart, CA, Kim, J, Pino, PA, Schnappinger, D, Read, KD, Encinas, L, Bates, RH, Wyatt, PG, Green, SR & Cleghorn, LAT 2025, 'Design and development of lysyl tRNA synthetase inhibitors, for the treatment of tuberculosis', Journal of Medicinal Chemistry, vol. 68, no. 15, pp. 16459-16482. https://doi.org/10.1021/acs.jmedchem.5c01331

TY - JOUR

T1 - Design and development of lysyl tRNA synthetase inhibitors, for the treatment of tuberculosis

AU - Davis, Susan H.

AU - Mathieson, Michael

AU - Buchanan, Kirsteen I.

AU - Dawson, Alice

AU - Smith, Alasdair

AU - Cocco, Mattia

AU - Tamaki, Fabio K.

AU - Post, John M.

AU - Baragaña, Beatriz

AU - Jansen, Chimed

AU - Kiczun, Michael

AU - Zuccotto, Fabio

AU - Wood, Gavin

AU - Scullion, Paul

AU - Ray, Peter C.

AU - Epemolu, Ola

AU - Lopez-Román, Eva Maria

AU - Guijarro López, Laura

AU - Engelhart, Curtis A.

AU - Kim, Jia

AU - Pino, Paula A.

AU - Schnappinger, Dirk

AU - Read, Kevin D.

AU - Encinas, Lourdes

AU - Bates, Robert H.

AU - Wyatt, Paul G.

AU - Green, Simon R.

AU - Cleghorn, Laura A. T.

PY - 2025/8/14

Y1 - 2025/8/14

N2 - There is currently a public health crisis due to the rise of multidrug-resistant tuberculosis cases, as well as the rise in the number of deaths from tuberculosis. To achieve the United Nations Sustainable Development Goal of ending the tuberculosis epidemic by 2030, new treatments are urgently required. We previously reported the discovery of 49, a preclinical candidate that acted through inhibition of the Mycobacterium tuberculosis lysyl tRNA synthetase (LysRS). In this report, the full medicinal chemistry program is reviewed from the original hit through to the optimized lead. The work was guided by the first crystal structures of M. tuberculosis LysRS. The physicochemical and pharmacokinetic properties were optimized to afford compounds suitable for evaluation in mouse efficacy models of tuberculosis and with the potential for clinical development.

AB - There is currently a public health crisis due to the rise of multidrug-resistant tuberculosis cases, as well as the rise in the number of deaths from tuberculosis. To achieve the United Nations Sustainable Development Goal of ending the tuberculosis epidemic by 2030, new treatments are urgently required. We previously reported the discovery of 49, a preclinical candidate that acted through inhibition of the Mycobacterium tuberculosis lysyl tRNA synthetase (LysRS). In this report, the full medicinal chemistry program is reviewed from the original hit through to the optimized lead. The work was guided by the first crystal structures of M. tuberculosis LysRS. The physicochemical and pharmacokinetic properties were optimized to afford compounds suitable for evaluation in mouse efficacy models of tuberculosis and with the potential for clinical development.

U2 - 10.1021/acs.jmedchem.5c01331

DO - 10.1021/acs.jmedchem.5c01331

M3 - Article

C2 - 40749104

SN - 0022-2623

VL - 68

SP - 16459

EP - 16482

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 15

ER -

Design and development of lysyl tRNA synthetase inhibitors, for the treatment of tuberculosis

Abstract

UN SDGs

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Projects

A Centre of Excellence for Lead Optimisation for Diseases of the Developing World (Joint funding by Wellcome & Gates)

State-of-the-Art Facilities for Structural Biology at the University of Dundee

Equipment

X-Ray Crystallography

Cite this