Identification of GSK3186899/DDD853651 as a Preclinical Development Candidate for the Treatment of Visceral Leishmaniasis

Michael G. Thomas; Manu De Rycker; Myriam Ajakane; Sébastian Albrecht; Ana Isabel Álvarez-Pedraglio; Markus Boesche; Stephen Brand; Lorna Campbell; Juan Cantizani-Perez; Laura A. T. Cleghorn; Royston C. B. Copley; Sabrinia D. Crouch; Alain Daugan; Gerard Drewes; Santiago Ferrer; Sonja Ghidelli-Disse; Silvia Gonzalez; Stephanie L. Gresham; Alan P. Hill; Sean J. Hindley; Rhiannon M. Lowe; Claire J. MacKenzie; Lorna MacLean; Sujatha Manthri; Franck Martin; Juan Miguel-Siles; Van Loc Nguyen; Suzanne Norval; Maria Osuna-Cabello; Andrew Woodland; Stephen Patterson; Imanol Pena; Maria Teresa Quesada-Campos; Iain H. Reid; Charlotte Revill; Jennifer Riley; Jose Ramon Ruiz-Gomez; Yoko Shishikura; Frederick R. C. Simeons; Alasdair Smith; Victoria C. Smith; Daniel Spinks; Laste Stojanovski; John Thomas; Stephen Thompson; Tim Underwood; David W. Gray; Jose M. Fiandor; Ian H. Gilbert; Paul G. Wyatt; Kevin D. Read; Timothy J. Miles

doi:10.1021/acs.jmedchem.8b01218

Identification of GSK3186899/DDD853651 as a Preclinical Development Candidate for the Treatment of Visceral Leishmaniasis

Michael G. Thomas, Manu De Rycker, Myriam Ajakane, Sébastian Albrecht, Ana Isabel Álvarez-Pedraglio, Markus Boesche, Stephen Brand, Lorna Campbell, Juan Cantizani-Perez, Laura A. T. Cleghorn, Royston C. B. Copley, Sabrinia D. Crouch, Alain Daugan, Gerard Drewes, Santiago Ferrer, Sonja Ghidelli-Disse, Silvia Gonzalez, Stephanie L. Gresham, Alan P. Hill, Sean J. HindleyRhiannon M. Lowe, Claire J. MacKenzie, Lorna MacLean, Sujatha Manthri, Franck Martin, Juan Miguel-Siles, Van Loc Nguyen, Suzanne Norval, Maria Osuna-Cabello, Andrew Woodland, Stephen Patterson, Imanol Pena, Maria Teresa Quesada-Campos, Iain H. Reid, Charlotte Revill, Jennifer Riley, Jose Ramon Ruiz-Gomez, Yoko Shishikura, Frederick R. C. Simeons, Alasdair Smith, Victoria C. Smith, Daniel Spinks, Laste Stojanovski, John Thomas, Stephen Thompson, Tim Underwood, David W. Gray, Jose M. Fiandor, Ian H. Gilbert, Paul G. Wyatt, Kevin D. Read, Timothy J. Miles

Research output: Contribution to journal › Article

4 Citations (Scopus)

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Abstract

The leishmaniases are diseases that affect millions of people across the world, in particular visceral leishmaniasis (VL) which is fatal unless treated. Current standard of care for VL suffers from multiple issues and there is a limited pipeline of new candidate drugs. As such, there is a clear unmet medical need to identify new treatments. This paper describes the optimization of a phenotypic hit against Leishmania donovani, the major causative organism of VL. The key challenges were to balance solubility and metabolic stability while maintaining potency. Herein, strategies to address these shortcomings and enhance efficacy are discussed, culminating in the discovery of preclinical development candidate GSK3186899/DDD853651 (1) for VL.

Original language	English
Pages (from-to)	1180-1202
Number of pages	23
Journal	Journal of Medicinal Chemistry
Volume	62
Issue number	3
Early online date	20 Dec 2018
DOIs	https://doi.org/10.1021/acs.jmedchem.8b01218
Publication status	Published - 14 Feb 2019

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Keywords

Leishmaniasis
visceral leishmaniasis
anti-visceral leishmaniasis agents
Cdc2-related kinase 12 (CRK12) inhibitor
neglected diseases

Cite this

Thomas, M. G., De Rycker, M., Ajakane, M., Albrecht, S., Álvarez-Pedraglio, A. I., Boesche, M., Brand, S., Campbell, L., Cantizani-Perez, J., Cleghorn, L. A. T., Copley, R. C. B., Crouch, S. D., Daugan, A., Drewes, G., Ferrer, S., Ghidelli-Disse, S., Gonzalez, S., Gresham, S. L., Hill, A. P., ... Miles, T. J. (2019). Identification of GSK3186899/DDD853651 as a Preclinical Development Candidate for the Treatment of Visceral Leishmaniasis. Journal of Medicinal Chemistry, 62(3), 1180-1202. https://doi.org/10.1021/acs.jmedchem.8b01218

Thomas, Michael G. ; De Rycker, Manu ; Ajakane, Myriam ; Albrecht, Sébastian ; Álvarez-Pedraglio, Ana Isabel ; Boesche, Markus ; Brand, Stephen ; Campbell, Lorna ; Cantizani-Perez, Juan ; Cleghorn, Laura A. T. ; Copley, Royston C. B. ; Crouch, Sabrinia D. ; Daugan, Alain ; Drewes, Gerard ; Ferrer, Santiago ; Ghidelli-Disse, Sonja ; Gonzalez, Silvia ; Gresham, Stephanie L. ; Hill, Alan P. ; Hindley, Sean J. ; Lowe, Rhiannon M. ; MacKenzie, Claire J. ; MacLean, Lorna ; Manthri, Sujatha ; Martin, Franck ; Miguel-Siles, Juan ; Nguyen, Van Loc ; Norval, Suzanne ; Osuna-Cabello, Maria ; Woodland, Andrew ; Patterson, Stephen ; Pena, Imanol ; Quesada-Campos, Maria Teresa ; Reid, Iain H. ; Revill, Charlotte ; Riley, Jennifer ; Ruiz-Gomez, Jose Ramon ; Shishikura, Yoko ; Simeons, Frederick R. C. ; Smith, Alasdair ; Smith, Victoria C. ; Spinks, Daniel ; Stojanovski, Laste ; Thomas, John ; Thompson, Stephen ; Underwood, Tim ; Gray, David W. ; Fiandor, Jose M. ; Gilbert, Ian H. ; Wyatt, Paul G. ; Read, Kevin D. ; Miles, Timothy J. / Identification of GSK3186899/DDD853651 as a Preclinical Development Candidate for the Treatment of Visceral Leishmaniasis. In: Journal of Medicinal Chemistry. 2019 ; Vol. 62, No. 3. pp. 1180-1202.

@article{a5774ff9c98b44c1a39674e617319eb7,

title = "Identification of GSK3186899/DDD853651 as a Preclinical Development Candidate for the Treatment of Visceral Leishmaniasis",

abstract = "The leishmaniases are diseases that affect millions of people across the world, in particular visceral leishmaniasis (VL) which is fatal unless treated. Current standard of care for VL suffers from multiple issues and there is a limited pipeline of new candidate drugs. As such, there is a clear unmet medical need to identify new treatments. This paper describes the optimization of a phenotypic hit against Leishmania donovani, the major causative organism of VL. The key challenges were to balance solubility and metabolic stability while maintaining potency. Herein, strategies to address these shortcomings and enhance efficacy are discussed, culminating in the discovery of preclinical development candidate GSK3186899/DDD853651 (1) for VL.",

keywords = "Leishmaniasis, visceral leishmaniasis, anti-visceral leishmaniasis agents, Cdc2-related kinase 12 (CRK12) inhibitor, neglected diseases",

author = "Thomas, {Michael G.} and {De Rycker}, Manu and Myriam Ajakane and S{\'e}bastian Albrecht and {\'A}lvarez-Pedraglio, {Ana Isabel} and Markus Boesche and Stephen Brand and Lorna Campbell and Juan Cantizani-Perez and Cleghorn, {Laura A. T.} and Copley, {Royston C. B.} and Crouch, {Sabrinia D.} and Alain Daugan and Gerard Drewes and Santiago Ferrer and Sonja Ghidelli-Disse and Silvia Gonzalez and Gresham, {Stephanie L.} and Hill, {Alan P.} and Hindley, {Sean J.} and Lowe, {Rhiannon M.} and MacKenzie, {Claire J.} and Lorna MacLean and Sujatha Manthri and Franck Martin and Juan Miguel-Siles and Nguyen, {Van Loc} and Suzanne Norval and Maria Osuna-Cabello and Andrew Woodland and Stephen Patterson and Imanol Pena and Quesada-Campos, {Maria Teresa} and Reid, {Iain H.} and Charlotte Revill and Jennifer Riley and Ruiz-Gomez, {Jose Ramon} and Yoko Shishikura and Simeons, {Frederick R. C.} and Alasdair Smith and Smith, {Victoria C.} and Daniel Spinks and Laste Stojanovski and John Thomas and Stephen Thompson and Tim Underwood and Gray, {David W.} and Fiandor, {Jose M.} and Gilbert, {Ian H.} and Wyatt, {Paul G.} and Read, {Kevin D.} and Miles, {Timothy J.}",

note = "Funding: Wellcome trust (nos. 092340 and 100476).",

year = "2019",

month = feb

day = "14",

doi = "10.1021/acs.jmedchem.8b01218",

language = "English",

volume = "62",

pages = "1180--1202",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "3",

}

Thomas, MG , De Rycker, M, Ajakane, M, Albrecht, S, Álvarez-Pedraglio, AI, Boesche, M, Brand, S, Campbell, L, Cantizani-Perez, J, Cleghorn, LAT, Copley, RCB, Crouch, SD, Daugan, A, Drewes, G, Ferrer, S, Ghidelli-Disse, S, Gonzalez, S, Gresham, SL, Hill, AP, Hindley, SJ, Lowe, RM, MacKenzie, CJ , MacLean, L , Manthri, S, Martin, F, Miguel-Siles, J, Nguyen, VL, Norval, S , Osuna-Cabello, M , Woodland, A , Patterson, S, Pena, I, Quesada-Campos, MT, Reid, IH, Revill, C, Riley, J, Ruiz-Gomez, JR, Shishikura, Y , Simeons, FRC, Smith, A, Smith, VC, Spinks, D, Stojanovski, L , Thomas, J , Thompson, S, Underwood, T, Gray, DW, Fiandor, JM, Gilbert, IH , Wyatt, PG , Read, KD & Miles, TJ 2019, 'Identification of GSK3186899/DDD853651 as a Preclinical Development Candidate for the Treatment of Visceral Leishmaniasis', Journal of Medicinal Chemistry, vol. 62, no. 3, pp. 1180-1202. https://doi.org/10.1021/acs.jmedchem.8b01218

Identification of GSK3186899/DDD853651 as a Preclinical Development Candidate for the Treatment of Visceral Leishmaniasis. / Thomas, Michael G.; De Rycker, Manu; Ajakane, Myriam; Albrecht, Sébastian; Álvarez-Pedraglio, Ana Isabel; Boesche, Markus; Brand, Stephen; Campbell, Lorna; Cantizani-Perez, Juan; Cleghorn, Laura A. T.; Copley, Royston C. B.; Crouch, Sabrinia D.; Daugan, Alain; Drewes, Gerard; Ferrer, Santiago; Ghidelli-Disse, Sonja; Gonzalez, Silvia; Gresham, Stephanie L.; Hill, Alan P.; Hindley, Sean J.; Lowe, Rhiannon M.; MacKenzie, Claire J.; MacLean, Lorna ; Manthri, Sujatha; Martin, Franck; Miguel-Siles, Juan; Nguyen, Van Loc; Norval, Suzanne ; Osuna-Cabello, Maria ; Woodland, Andrew ; Patterson, Stephen; Pena, Imanol; Quesada-Campos, Maria Teresa; Reid, Iain H.; Revill, Charlotte; Riley, Jennifer; Ruiz-Gomez, Jose Ramon; Shishikura, Yoko ; Simeons, Frederick R. C.; Smith, Alasdair; Smith, Victoria C.; Spinks, Daniel; Stojanovski, Laste ; Thomas, John ; Thompson, Stephen; Underwood, Tim; Gray, David W.; Fiandor, Jose M.; Gilbert, Ian H.; Wyatt, Paul G. (Lead / Corresponding author); Read, Kevin D. (Lead / Corresponding author); Miles, Timothy J. (Lead / Corresponding author).

In: Journal of Medicinal Chemistry, Vol. 62, No. 3, 14.02.2019, p. 1180-1202.

Research output: Contribution to journal › Article

TY - JOUR

T1 - Identification of GSK3186899/DDD853651 as a Preclinical Development Candidate for the Treatment of Visceral Leishmaniasis

AU - Thomas, Michael G.

AU - De Rycker, Manu

AU - Ajakane, Myriam

AU - Albrecht, Sébastian

AU - Álvarez-Pedraglio, Ana Isabel

AU - Boesche, Markus

AU - Brand, Stephen

AU - Campbell, Lorna

AU - Cantizani-Perez, Juan

AU - Cleghorn, Laura A. T.

AU - Copley, Royston C. B.

AU - Crouch, Sabrinia D.

AU - Daugan, Alain

AU - Drewes, Gerard

AU - Ferrer, Santiago

AU - Ghidelli-Disse, Sonja

AU - Gonzalez, Silvia

AU - Gresham, Stephanie L.

AU - Hill, Alan P.

AU - Hindley, Sean J.

AU - Lowe, Rhiannon M.

AU - MacKenzie, Claire J.

AU - MacLean, Lorna

AU - Manthri, Sujatha

AU - Martin, Franck

AU - Miguel-Siles, Juan

AU - Nguyen, Van Loc

AU - Norval, Suzanne

AU - Osuna-Cabello, Maria

AU - Woodland, Andrew

AU - Patterson, Stephen

AU - Pena, Imanol

AU - Quesada-Campos, Maria Teresa

AU - Reid, Iain H.

AU - Revill, Charlotte

AU - Riley, Jennifer

AU - Ruiz-Gomez, Jose Ramon

AU - Shishikura, Yoko

AU - Simeons, Frederick R. C.

AU - Smith, Alasdair

AU - Smith, Victoria C.

AU - Spinks, Daniel

AU - Stojanovski, Laste

AU - Thomas, John

AU - Thompson, Stephen

AU - Underwood, Tim

AU - Gray, David W.

AU - Fiandor, Jose M.

AU - Gilbert, Ian H.

AU - Wyatt, Paul G.

AU - Read, Kevin D.

AU - Miles, Timothy J.

N1 - Funding: Wellcome trust (nos. 092340 and 100476).

PY - 2019/2/14

Y1 - 2019/2/14

N2 - The leishmaniases are diseases that affect millions of people across the world, in particular visceral leishmaniasis (VL) which is fatal unless treated. Current standard of care for VL suffers from multiple issues and there is a limited pipeline of new candidate drugs. As such, there is a clear unmet medical need to identify new treatments. This paper describes the optimization of a phenotypic hit against Leishmania donovani, the major causative organism of VL. The key challenges were to balance solubility and metabolic stability while maintaining potency. Herein, strategies to address these shortcomings and enhance efficacy are discussed, culminating in the discovery of preclinical development candidate GSK3186899/DDD853651 (1) for VL.

AB - The leishmaniases are diseases that affect millions of people across the world, in particular visceral leishmaniasis (VL) which is fatal unless treated. Current standard of care for VL suffers from multiple issues and there is a limited pipeline of new candidate drugs. As such, there is a clear unmet medical need to identify new treatments. This paper describes the optimization of a phenotypic hit against Leishmania donovani, the major causative organism of VL. The key challenges were to balance solubility and metabolic stability while maintaining potency. Herein, strategies to address these shortcomings and enhance efficacy are discussed, culminating in the discovery of preclinical development candidate GSK3186899/DDD853651 (1) for VL.

KW - Leishmaniasis

KW - visceral leishmaniasis

KW - anti-visceral leishmaniasis agents

KW - Cdc2-related kinase 12 (CRK12) inhibitor

KW - neglected diseases

UR - http://www.scopus.com/inward/record.url?scp=85059362983&partnerID=8YFLogxK

U2 - 10.1021/acs.jmedchem.8b01218

DO - 10.1021/acs.jmedchem.8b01218

M3 - Article

C2 - 30570265

VL - 62

SP - 1180

EP - 1202

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 3

ER -

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Final Published VersionFinal published version, 7.3 MBLicence: CC BY

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Identification of GSK3186899/DDD853651 as a Preclinical Development Candidate for the Treatment of Visceral Leishmaniasis

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