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鉴定和优化具有抗结核活性的聚酮合酶 13 硫酯酶结构域的新型抑制剂。

Identification and Optimization of Novel Inhibitors of the Polyketide Synthase 13 Thioesterase Domain with Antitubercular Activity.

机构信息

Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K.

Global Health Medicines R&D, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, 28760 Madrid Spain.

出版信息

J Med Chem. 2023 Nov 23;66(22):15380-15408. doi: 10.1021/acs.jmedchem.3c01514. Epub 2023 Nov 10.

DOI:10.1021/acs.jmedchem.3c01514
PMID:37948640
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10683028/
Abstract

There is an urgent need for new tuberculosis (TB) treatments, with novel modes of action, to reduce the incidence/mortality of TB and to combat resistance to current treatments. Through both chemical and genetic methodologies, polyketide synthase 13 (Pks13) has been validated as essential for mycobacterial survival and as an attractive target for growth inhibitors. A benzofuran series of inhibitors that targeted the Pks13 thioesterase domain, failed to progress to preclinical development due to concerns over cardiotoxicity. Herein, we report the identification of a novel oxadiazole series of Pks13 inhibitors, derived from a high-throughput screening hit and structure-guided optimization. This new series binds in the Pks13 thioesterase domain, with a distinct binding mode compared to the benzofuran series. Through iterative rounds of design, assisted by structural information, lead compounds were identified with improved antitubercular potencies (MIC < 1 μM) and ADMET profiles.

摘要

目前迫切需要新的结核病（TB）治疗方法，具有新的作用模式，以降低结核病的发病率/死亡率，并对抗当前治疗方法的耐药性。通过化学和遗传方法，聚酮合酶 13（Pks13）已被验证对分枝杆菌的生存至关重要，并且是生长抑制剂的有吸引力的靶标。一系列针对 Pks13 硫酯酶结构域的苯并呋喃抑制剂由于担心心脏毒性而未能进入临床前开发。在此，我们报告了一种新型噁二唑系列 Pks13 抑制剂的鉴定，该抑制剂源自高通量筛选命中和基于结构的优化。与苯并呋喃系列相比，这个新系列在 Pks13 硫酯酶结构域中具有独特的结合模式。通过结构信息辅助的迭代设计，确定了具有改善的抗结核活性（MIC <1 μM）和 ADMET 谱的先导化合物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4541/10683028/e5fc75111779/jm3c01514_0003.jpg
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Structure and dynamics of the essential endogenous mycobacterial polyketide synthase Pks13.必需内生源分枝杆菌聚酮合酶 Pks13 的结构与动态。
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Lysyl-tRNA synthetase, a target for urgently needed M. tuberculosis drugs.赖氨酸 tRNA 合成酶，一种急需的结核分枝杆菌药物靶标。
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ACS Infect Dis. 2024 May 10;10(5):1561-1575. doi: 10.1021/acsinfecdis.3c00592. Epub 2024 Apr 5.
Nat Commun. 2022 Oct 11;13(1):5992. doi: 10.1038/s41467-022-33736-5.
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Structure-Based Optimization of Coumestan Derivatives as Polyketide Synthase 13-Thioesterase(Pks13-TE) Inhibitors with Improved hERG Profiles for Treatment.基于结构的美洲大蠊衍生化合物的优化作为聚酮合酶 13-硫酯酶（Pks13-TE）抑制剂，改善 hERG 谱，用于治疗。
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Oxadiazole: A highly versatile scaffold in drug discovery.恶二唑：药物发现中极具多功能性的支架。
Arch Pharm (Weinheim). 2022 Sep;355(9):e2200123. doi: 10.1002/ardp.202200123. Epub 2022 May 16.
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