7M7V

Crystal Structure of Mtb Pks13 Thioesterase domain in complex with Compound 6

Summary for 7M7V

• Entry DOI: 10.2210/pdb7m7v/pdb
• Descriptor: Polyketide synthase Pks13, 5-hydroxy-2-(4-hydroxyphenyl)-N-methyl-4-[(2-oxa-6-azaspiro[3.4]octan-6-yl)methyl]-1-benzofuran-3-carboxamide (3 entities in total)
• Functional Keywords: thioesterase domain, compound 6 complex, pks13, mycobacterium, polyketide synthase, mycolic acid condensation, alpha/beta hydrolase, thioesterase, transferase-transferase inhibitor complex, transferase, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 2
• Total formula weight: 64372.38

Authors

Aggarwal, A.,Sacchettini, J.C. (deposition date: 2021-03-29, release date: 2022-02-16, Last modification date: 2023-10-18)

Primary citation

Wilson, C.,Ray, P.,Zuccotto, F.,Hernandez, J.,Aggarwal, A.,Mackenzie, C.,Caldwell, N.,Taylor, M.,Huggett, M.,Mathieson, M.,Murugesan, D.,Smith, A.,Davis, S.,Cocco, M.,Parai, M.K.,Acharya, A.,Tamaki, F.,Scullion, P.,Epemolu, O.,Riley, J.,Stojanovski, L.,Lopez-Roman, E.M.,Torres-Gomez, P.A.,Toledo, A.M.,Guijarro-Lopez, L.,Camino, I.,Engelhart, C.A.,Schnappinger, D.,Massoudi, L.M.,Lenaerts, A.,Robertson, G.T.,Walpole, C.,Matthews, D.,Floyd, D.,Sacchettini, J.C.,Read, K.D.,Encinas, L.,Bates, R.H.,Green, S.R.,Wyatt, P.G.
Optimization of TAM16, a Benzofuran That Inhibits the Thioesterase Activity of Pks13; Evaluation toward a Preclinical Candidate for a Novel Antituberculosis Clinical Target.
J.Med.Chem., 65:409-423, 2022

PubMed Abstract: 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 was identified as a potential lead for TB inhibiting a novel target, the thioesterase domain of Pks13. Although, having promising activity against , 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.

PubMed: 34910486
DOI: 10.1021/acs.jmedchem.1c01586

Experimental method

X-RAY DIFFRACTION (2.29 Å)