Optimization of TAM16, a Benzofuran That Inhibits the Thioesterase Activity of Pks13; Evaluation toward a Preclinical Candidate for a Novel Antituberculosis Clinical Target

TY - JOUR

T1 - Optimization of TAM16, a Benzofuran That Inhibits the Thioesterase Activity of Pks13; Evaluation toward a Preclinical Candidate for a Novel Antituberculosis Clinical Target

AU - Wilson, Caroline

AU - Ray, Peter

AU - Zuccotto, Fabio

AU - Hernandez, Jorge

AU - Aggarwal, Anup

AU - Mackenzie, Claire

AU - Caldwell, Nicola

AU - Taylor, Malcolm

AU - Huggett, Margaret

AU - Mathieson, Michael

AU - Murugesan, Dinakaran

AU - Smith, Alasdair

AU - Davis, Susan

AU - Cocco, Mattia

AU - Parai, Maloy K.

AU - Acharya, Arjun

AU - Tamaki, Fabio

AU - Scullion, Paul

AU - Epemolu, Ola

AU - Riley, Jennifer

AU - Stojanovski, Laste

AU - Lopez-román, Eva Maria

AU - Torres-Gómez, Pedro Alfonso

AU - Toledo, Ana Maria

AU - Guijarro-Lopez, Laura

AU - Camino, Isabel

AU - Engelhart, Curtis A.

AU - Schnappinger, Dirk

AU - Massoudi, Lisa M.

AU - Lenaerts, Anne

AU - Robertson, Gregory T.

AU - Walpole, Chris

AU - Matthews, David

AU - Floyd, David

AU - Sacchettini, James C.

AU - Read, Kevin D.

AU - Encinas, Lourdes

AU - Bates, Robert H.

AU - Green, Simon R.

AU - Wyatt, Paul G.

N1 - This work was funded in part by: an award to PGW from the Bill and Melinda Gates Foundation (OPP1066891) and Wellcome Trust, (100195/Z/12/Z); an award to D.S. from B&MGF (OPP1024065); an award to C.W. from B&MGF (OPP1032548); an award to AJL/GTR from B&MGF (OPP1126594 and INV-009105) and awards to J.C.S. from B&MGF (INV002178), NIAID-NIH (TB Structural Genomics grant P01A1095208) and Welch foundation (A0015)

PY - 2022/1/13

Y1 - 2022/1/13

N2 - With increasing drug resistance in tuberculosis (TB) patient populations, there is an urgent need for new drugs. Ideally, new agents should work through novel targets so that they are unencumbered by preexisting clinical resistance to current treatments. Benzofuran 1 was identified as a potential lead for TB inhibiting a novel target, the thioesterase domain of Pks13. Although, having promising activity against Mycobacterium tuberculosis, its main liability was inhibition of the hERG cardiac ion channel. This article describes the optimization of the series toward a preclinical candidate. Despite improvements in the hERG liability in vitro, when new compounds were assessed in ex vivo cardiotoxicity models, they still induced cardiac irregularities. Further series development was stopped because of concerns around an insufficient safety window. However, the demonstration of in vivo activity for multiple series members further validates Pks13 as an attractive novel target for antitubercular drugs and supports development of alternative chemotypes.

AB - With increasing drug resistance in tuberculosis (TB) patient populations, there is an urgent need for new drugs. Ideally, new agents should work through novel targets so that they are unencumbered by preexisting clinical resistance to current treatments. Benzofuran 1 was identified as a potential lead for TB inhibiting a novel target, the thioesterase domain of Pks13. Although, having promising activity against Mycobacterium tuberculosis, its main liability was inhibition of the hERG cardiac ion channel. This article describes the optimization of the series toward a preclinical candidate. Despite improvements in the hERG liability in vitro, when new compounds were assessed in ex vivo cardiotoxicity models, they still induced cardiac irregularities. Further series development was stopped because of concerns around an insufficient safety window. However, the demonstration of in vivo activity for multiple series members further validates Pks13 as an attractive novel target for antitubercular drugs and supports development of alternative chemotypes.

UR - https://www.scopus.com/pages/publications/85121923821

U2 - 10.1021/acs.jmedchem.1c01586

DO - 10.1021/acs.jmedchem.1c01586

M3 - Article

C2 - 34910486

SN - 0022-2623

VL - 65

SP - 409

EP - 423

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 1

ER -