Delving into the Latest Updates on TBA-7371 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

DprE1

Mechanism

DprE1 inhibitors(FAD-dependent decaprenylphosphoryl-beta-D-ribofuranose 2-oxidase inhibitors)

Therapeutic Areas

Infectious DiseasesRespiratory Diseases

Active Indication

Pulmonary Tuberculosis

Inactive Indication-

Originator Organization

AstraZeneca Pharmaceuticals Co. Ltd.

Active Organization

AstraZeneca Pharmaceuticals Co. Ltd.

Global Alliance for TB Drug Development

Foundation For Neglected Disease Research

+ [1]

Inactive Organization-

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC18H21N5O3

InChIKeyVDRYGTNDKXIPSK-UHFFFAOYSA-N

CAS Registry1494675-86-3

ABSTRACTThe combination of bedaquiline, pretomanid, and linezolid (BPaL) has become a preferred regimen for treating multidrug- and extensively drug-resistant tuberculosis (TB). However, treatment-limiting toxicities of linezolid and reports of emerging bedaquiline and pretomanid resistance necessitate efforts to develop new short-course oral regimens. We recently found that the addition of GSK2556286 increases the bactericidal and sterilizing activity of BPa-containing regimens in a well-established BALB/c mouse model of tuberculosis. Here, we used this model to evaluate the potential of new regimens combining bedaquiline or the more potent diarylquinoline TBAJ-587 with GSK2556286 and the DprE1 inhibitor TBA-7371, all of which are currently in early-phase clinical trials. We found the combination of bedaquiline, GSK2556286, and TBA-7371 to be more active than the first-line regimen and nearly as effective as BPaL in terms of bactericidal and sterilizing activity. In addition, we found that GSK2556286 and TBA-7371 were as effective as pretomanid and the novel oxazolidinone TBI-223 when either drug pair was combined with TBAJ-587 and that the addition of GSK2556286 increased the bactericidal activity of the TBAJ-587, pretomanid, and TBI-223 combination. We conclude that GSK2556286 and TBA-7371 have the potential to replace pretomanid, an oxazolidinone, or both components, in combination with bedaquiline or TBAJ-587.

08 Feb 2024·Journal of Medicinal ChemistryQ1 · MEDICINE

Discovery of N-(1-(6-Oxo-1,6-dihydropyrimidine)-pyrazole) Acetamide Derivatives as Novel Noncovalent DprE1 Inhibitors against Mycobacterium tuberculosis

Q1 · MEDICINE

Article

Author: Alam, Md Shah ; Zhang, Tianyu ; Hou, Tingjun ; Kang, Yu ; Dong, Xiaowu ; Che, Jinxin ; Lu, Yang ; Li, Dan ; Lei, Yixuan ; Ma, WanLi ; Hu, Xueping ; Xu, Yaping ; Ye, Qing ; Xu, Ruolan ; Yang, Liu ; Chai, Xin

Decaprenylphosphoryl-β-d-ribose oxidase (DprE1) is a promising target for treating tuberculosis (TB). Currently, most novel DprE1 inhibitors are discovered through high-throughput screening, while computer-aided drug design (CADD) strategies are expected to promote the discovery process. In this study, with the aid of structure-based virtual screening and computationally guided design, a series of novel scaffold N-(1-(6-oxo-1,6-dihydropyrimidine)-pyrazole) acetamide derivatives with significant antimycobacterial activities were identified. Among them, compounds LK-60 and LK-75 are capable of effectively suppressing the proliferation of Mtb with MIC_Mtb values of 0.78-1.56 μM, comparable with isoniazid and much superior to the phase II candidate TBA-7371 (MIC_Mtb = 12.5 μM). LK-60 is also the most active DprE1 inhibitor derived from CADD so far. Further studies confirmed their high affinity to DprE1, good safety profiles to gut microbiota and human cells, and synergy effects with either rifampicin or ethambutol, indicating their broad potential for clinical applications.

01 Jan 2024·Bioinformatics and Biology Insights

Targeting decaprenylphosphoryl-β-D-ribose 2′-epimerase for Innovative Drug Development Against Mycobacterium Tuberculosis Drug-Resistant Strains

Article

Author: El Haddoumi, Ghyzlane ; Belyamani, Lahcen ; Kourou, Jouhaina ; Ibrahimi, Azeddine ; Mansouri, Mariam ; Kandoussi, Ilham

Tuberculosis (TB) remains a global health challenge with the emergence of drug-resistant Mycobacterium tuberculosis variants, necessitating innovative drug molecules. One potential target is the cell wall synthesis enzyme decaprenylphosphoryl-β-D-ribose 2′-epimerase (DprE1), crucial for virulence and survival. This study employed virtual screening of 111 Protein Data Bank (PDB) database molecules known for their inhibitory biological activity against DprE1 with known IC50 values. Six compounds, PubChem ID: 390820, 86287492, 155294899, 155522922, 162651615, and 162665075, exhibited promising attributes as drug candidates and validated against clinical trial inhibitors BTZ043, TBA-7371, PBTZ169, and OPC-167832. Concurrently, this research focused on DprE1 mutation effects using molecular dynamic simulations. Among the 10 mutations tested, C387N significantly influenced protein behavior, leading to structural alterations observed through root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), radius of gyration (Rg), and solvent-accessible surface area (SASA) analysis. Ligand 2 (ID: 390820) emerged as a promising candidate through ligand-based pharmacophore analysis, displaying enhanced binding compared with reference inhibitors. Molecular dynamic simulations highlighted ligand 2’s interaction with the C387N mutation, reducing fluctuations, augmenting hydrogen bonding, and influencing solvent accessibility. These collective findings emphasize ligand 2’s efficacy, particularly against severe mutations, in enhancing protein-ligand complex stability. Integrated computational and pharmacophore methodologies offer valuable insights into drug candidates and their interactions within intricate protein environments. This research lays a strategic foundation for targeted interventions against drug-resistant TB, highlighting ligand 2’s potential for advanced drug development strategies.

100 Deals associated with TBA-7371

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB16243

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Pulmonary Tuberculosis	Phase 2	-	AstraZeneca Pharmaceuticals Co. Ltd.	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04176250 (CTgov)	Phase 2	Pulmonary Tuberculosis	93	TBA-7371 (TBA-7371 100 mg QD)	piujuvojmr(gpwayjfipf) = qmsyipgxdi dzozeoqcls (oioommpgfm, jcngxsmhgn - zocgzrliub) View more	-	11 Apr 2024
				TBA-7371 (TBA-7371 100 mg BID)	piujuvojmr(gpwayjfipf) = trjrsgtmic dzozeoqcls (oioommpgfm, hjbefvlxxs - sdxflpxrde) View more