Last update 01 Nov 2024

TbHK1

Last update 01 Nov 2024

Basic Info

Synonyms-

Introduction-

Drugs associated with TbHK1

ML205

Target

TbHK1

Mechanism

TbHK1 inhibitors

Active Org.

University of Pittsburgh

Originator Org.

University of Pittsburgh

Active Indication

Trypanosomiasis, African

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with TbHK1

100 Translational Medicine associated with TbHK1

0 Patents (Medical) associated with TbHK1

Literatures (Medical) associated with TbHK1

07 Dec 2017·ChemMedChemQ3 · MEDICINE

Optimization and Evaluation of Antiparasitic Benzamidobenzoic Acids as Inhibitors of Kinetoplastid Hexokinase 1

Q3 · MEDICINE

Article

Author: Hackler, Amber L. ; Aubé, Jeffrey ; Weiner, Warren S. ; Harris, Michael T. ; Flaherty, Daniel P. ; Kahney, Elizabeth W. ; Schroeder, Chad E. ; Khan, Haaris ; Morris, James C. ; Sharlow, Elizabeth R. ; Patrick, Stephen L. ; Golden, Jennifer E.

AbstractKinetoplastid‐based infections are neglected diseases that represent a significant human health issue. Chemotherapeutic options are limited due to toxicity, parasite susceptibility, and poor patient compliance. In response, we studied a molecular‐target‐directed approach involving intervention of hexokinase activity—a pivotal enzyme in parasite metabolism. A benzamidobenzoic acid hit with modest biochemical inhibition of Trypanosoma brucei hexokinase 1 (TbHK1, IC50=9.1 μm), low mammalian cytotoxicity (IMR90 cells, EC50>25 μm), and no appreciable activity on whole bloodstream‐form (BSF) parasites was optimized to afford a probe with improved TbHK1 potency and, significantly, efficacy against whole BSF parasites (TbHK1, IC50=0.28 μm; BSF, ED50=1.9 μm). Compounds in this series also inhibited the hexokinase enzyme from Leishmania major (LmHK1), albeit with less potency than toward TbHK1, suggesting that inhibition of the glycolytic pathway may be a promising opportunity to target multiple disease‐causing trypanosomatid protozoa.

01 Feb 2017·Bioorganic & Medicinal Chemistry LettersQ4 · MEDICINE

Evaluation of substituted ebselen derivatives as potential trypanocidal agents

Q4 · MEDICINE

Article

Author: Morris, James C ; Hackler, Amber L ; Patrick, Stephen L ; Anayee, Mark ; Golden, Jennifer E ; Gordhan, Heeren M ; Whitehead, Daniel C ; Swasy, Maria I

Human African trypanosomiasis is a disease of sub-Saharan Africa, where millions are at risk for the illness. The disease, commonly referred to as African sleeping sickness, is caused by an infection by the eukaryotic pathogen, Trypanosoma brucei. Previously, a target-based high throughput screen revealed ebselen (EbSe), and its sulfur analog, EbS, to be potent in vitro inhibitors of the T. brucei hexokinase 1 (TbHK1). These molecules also exhibited potent trypanocidal activity in vivo. In this manuscript, we synthesized a series of sixteen EbSe and EbS derivatives bearing electron-withdrawing carboxylic acid and methyl ester functional groups, and evaluated the influence of these substituents on the biological efficacy of the parent scaffold. With the exception of one methyl ester derivative, these modifications ablated or blunted the potent TbHK1 inhibition of the parent scaffold. Nonetheless, a few of the methyl ester derivatives still exhibited trypanocidal effects with single-digit micromolar or high nanomolar EC₅₀ values.

01 Dec 2013·International Journal for Parasitology: Drugs and Drug ResistanceQ2 · MEDICINE

Exploring the mode of action of ebselen in Trypanosoma brucei hexokinase inhibition

Q2 · MEDICINE

ArticleOA

Author: Morris, James C ; Maselli, Andrew G ; Dodson, Heidi C ; Kahney, Elizabeth W ; Harris, Michael T ; Whitehead, Daniel C ; Joice, April C

Glycolysis is essential to Trypanosoma brucei, the causative agent of African sleeping sickness, suggesting enzymes in the pathway could be targets for drug development. Ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one, EbSe) was identified in a screen as a potent inhibitor of T. brucei hexokinase 1 (TbHK1), the first enzyme in the pathway. EbSe has a history of promiscuity as an enzyme inhibitor, inactivating proteins through seleno-sulfide conjugation with Cys residues. Indeed, dilution of TbHK1 and inhibitor following incubation did not temper inhibition suggesting conjugate formation. Using mass spectrometry to analyze EbSe-based modifications revealed that two Cys residues (C327 and C369) were oxidized after treatment. Site-directed mutagenesis of C327 led to enzyme inactivation indicating that C327 was essential for catalysis. C369 was not essential, suggesting that EbSe inhibition of TbHK1 was the consequence of modification of C327 via thiol oxidation. Additionally, neither EbSe treatment nor mutation of the nine TbHK1 Cys residues appreciably altered enzyme quaternary structure.

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TbHK1

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