Polypharmacology in Drug Development: A Minireview of Current Technologies

Tan, Zhi; Chaudhai, Rajan; Zhang, Shuxing

doi:10.1002/cmdc.201600067

Cited by 44 publications

(19 citation statements)

References 106 publications

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“…Meanwhile, CoMSIA-SIMCA classification model provided a platform to conduct efficient primary screening of potential TNIK inhibitors. As part of the recent polypharmacology and drug repurposing efforts 24 25 such comprehensive studies and the resultant models are ready to be used for compound repositioning against other targets.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Modeling and Discovery of Mebendazole as a Novel TRAF2- and NCK-interacting Kinase Inhibitor

Tan

Chen

Zhang

2016

Sci Rep

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TRAF2- and NCK-interacting kinase (TNIK) represents one of the crucial targets for Wnt-activated colorectal cancer. In this study, we curated two datasets and conducted a comprehensive modeling study to explore novel TNIK inhibitors with desirable biopharmaceutical properties. With Dataset I, we derived Comparative Molecular Similarity Indices Analysis (CoMSIA) and variable-selection k-nearest neighbor models, from which 3D-molecular fields and 2D-descriptors critical for the TNIK inhibitor activity were revealed. Based on Dataset II, predictive CoMSIA-SIMCA (Soft Independent Modelling by Class Analogy) models were obtained and employed to screen 1,448 FDA-approved small molecule drugs. Upon experimental evaluations, we discovered that mebendazole, an approved anthelmintic drug, could selectively inhibit TNIK kinase activity with a dissociation constant Kd = ~1 μM. The subsequent CoMSIA and kNN analyses indicated that mebendazole bears the favorable molecular features that are needed to bind and inhibit TNIK.

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Section: Discussionmentioning

confidence: 99%

Comprehensive Modeling and Discovery of Mebendazole as a Novel TRAF2- and NCK-interacting Kinase Inhibitor

Tan

Chen

Zhang

2016

Sci Rep

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“…As for multi-target approaches (also known as polypharmacology), it is gaining attention in the field of drug discovery, especially for complex diseases like cancers because of significant advantages [48][49][50][51][52][53][54]. To begin with, if we can address multiple targets with just one drug, we will have less issues with pharmacokinetics and/or drug resistance.…”

Section: Discussionmentioning

confidence: 99%

Discovery of Novel Inhibitors Targeting Multi-UDP-hexose Pyrophosphorylases as Anticancer Agents

et al. 2020

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To minimize treatment toxicities, recent anti-cancer research efforts have switched from broad-based chemotherapy to targeted therapy, and emerging data show that altered cellular metabolism in cancerous cells can be exploited as new venues for targeted intervention. In this study, we focused on, among the altered metabolic processes in cancerous cells, altered glycosylation due to its documented roles in cancer tumorigenesis, metastasis and drug resistance. We hypothesize that the enzymes required for the biosynthesis of UDP-hexoses, glycosyl donors for glycan synthesis, could serve as therapeutic targets for cancers. Through structure-based virtual screening and kinetic assay, we identified a drug-like chemical fragment, GAL-012, that inhibit a small family of UDP-hexose pyrophosphorylases-galactose pyro-phosphorylase (GALT), UDP-glucose pyrophosphorylase (UGP2) and UDP-N-acetylglucosamine pyrophosphorylase (AGX1/UAP1) with an IC50 of 30 µM. The computational docking studies supported the interaction of GAL-012 to the binding sites of GALT at Trp190 and Ser192, UGP2 at Gly116 and Lys127, and AGX1/UAP1 at Asn327 and Lys407, respectively. One of GAL-012 derivatives GAL-012-2 also demonstrated the inhibitory activity against GALT and UGP2. Moreover, we showed that GAL-012 suppressed the growth of PC3 cells in a dose-dependent manner with an EC50 of 75 µM with no effects on normal skin fibroblasts at 200 µM. Western blot analysis revealed reduced expression of pAKT (Ser473), pAKT (Thr308) by 77% and 72%, respectively in the treated cells. siRNA experiments against the respective genes encoding the pyrophosphorylases were also performed and the results further validated the proposed roles in cancer growth inhibition. Finally, synergistic relationships between GAL-012 and tunicamycin, as well as bortezomib (BTZ) in killing cultured cancer cells were observed, respectively. With its unique scaffold and relatively small size, GAL-012 serves as a promising early chemotype for optimization to become a safe, effective, multi-target anti-cancer drug candidate which could be used alone or in combination with known therapeutics.

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“…Workman and Collins have written about the ideal properties for a chemical probe, guided principally by experiences in the oncology field (17). We choose to focus more generally on what we term chemical tools, which may or may not exhibit polypharmacology (18,19) and may seed a drug discovery effort, in addition to increasing our basic understanding of fundamental biology. Rather than relying solely on Lipinski's rule of five (20), which while based on orally bioavailable drugs across many therapeutic areas may best be applied to filtering large libraries for initial screens and/or prioritizing the resulting set of hits (17), we suggest guidelines for compound profile parameters for antitubercular agents that should help to usher an optimization effort toward compounds that are active in vivo.…”

Section: Discussionmentioning

confidence: 99%

Novel Pyrimidines as Antitubercular Agents

Inoyama

Paget

Russo

et al. 2018

Antimicrob Agents Chemother

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infection is responsible for a global pandemic. New drugs are needed that do not show cross-resistance with the existing front-line therapeutics. A triazine antitubercular hit led to the design of a related pyrimidine family. The synthesis of a focused series of these analogs facilitated exploration of their activity, cytotoxicity, and physiochemical and absorption-distribution-metabolism-excretion properties. Select pyrimidines were then evaluated for their pharmacokinetic profiles in mice. The findings suggest a rationale for the further evolution of this promising series of antitubercular small molecules, which appear to share some similarities with the clinical compound PA-824 in terms of activation, while highlighting more general guidelines for the optimization of small-molecule antitubercular agents.

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Polypharmacology in Drug Development: A Minireview of Current Technologies

Cited by 44 publications

References 106 publications

Comprehensive Modeling and Discovery of Mebendazole as a Novel TRAF2- and NCK-interacting Kinase Inhibitor

Comprehensive Modeling and Discovery of Mebendazole as a Novel TRAF2- and NCK-interacting Kinase Inhibitor

Discovery of Novel Inhibitors Targeting Multi-UDP-hexose Pyrophosphorylases as Anticancer Agents

Novel Pyrimidines as Antitubercular Agents

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