A Small Molecule Screen Identifies Selective Inhibitors of Urea Transporter UT-A

Background: Tankyrases are known for their multifunctionalities within the poly(ADPribose) polymerases family and playing vital roles in various cellular processes which include the regulation of tumour suppressors. Tankyrases, which exist in two isoforms; Tankyrase 1 and 2, are highly homologous and an integral part of the Wnt β -catenin pathway that becomes overly dysregulated when hijacked by pro-carcinogenic machineries. Methods: In this review, we cover the distinct roles of the Tankyrase isoforms and their involvement in the disease pathogenesis. Also, we provide updates on experimentally and computationally derived antagonists of Tankyrase whilst highlighting the precedence of integrative computer-aided drug design methods towards the discovery of selective inhibitors. Results: Despite the high prospects embedded in the therapeutic targeting and blockade of Tankyrase isoforms, the inability of small molecule inhibitors to achieve selective targeting has remained a major setback, even until date. This explains numerous incessant drug design efforts geared towards the development of highly selective inhibitors of the respective Tankyrase isoforms since they mediate distinct aberrancies in disease progression. Therefore, considering the setbacks of conventional drug design methods, can computer-aided approaches actually save the day? Conclusion: The implementation of computer-aided drug design techniques in Tankyrase research could help complement experimental methods and facilitate ligand/structure-based design and discovery of small molecule inhibitors with enhanced selectivity.

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A survey of the kinome pharmacopeia reveals multiple scaffolds and targets for the development of novel anthelmintics

Scientific Reports ◽

10.1038/s41598-021-88150-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Jessica Knox ◽

Nicolas Joly ◽

Edmond M. Linossi ◽

José A. Carmona-Negrón ◽

Natalia Jura ◽

...

Keyword(s):

Caenorhabditis Elegans ◽

Developmental Delay ◽

Small Molecule ◽

Parasitic Nematode ◽

Kinase Inhibitor ◽

Binding Pocket ◽

Drug Binding ◽

Nematode Infection ◽

Selective Inhibitors ◽

C Elegans

AbstractOver one billion people are currently infected with a parasitic nematode. Symptoms can include anemia, malnutrition, developmental delay, and in severe cases, death. Resistance is emerging to the anthelmintics currently used to treat nematode infection, prompting the need to develop new anthelmintics. Towards this end, we identified a set of kinases that may be targeted in a nematode-selective manner. We first screened 2040 inhibitors of vertebrate kinases for those that impair the model nematode Caenorhabditis elegans. By determining whether the terminal phenotype induced by each kinase inhibitor matched that of the predicted target mutant in C. elegans, we identified 17 druggable nematode kinase targets. Of these, we found that nematode EGFR, MEK1, and PLK1 kinases have diverged from vertebrates within their drug-binding pocket. For each of these targets, we identified small molecule scaffolds that may be further modified to develop nematode-selective inhibitors. Nematode EGFR, MEK1, and PLK1 therefore represent key targets for the development of new anthelmintic medicines.

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Small-Molecule Screen Identifies De Novo Nucleotide Synthesis as a Vulnerability of Cells Lacking SIRT3

Cell Reports ◽

10.1016/j.celrep.2018.01.076 ◽

2018 ◽

Vol 22 (8) ◽

pp. 1945-1955 ◽

Cited By ~ 7

Author(s):

Karina N. Gonzalez Herrera ◽

Elma Zaganjor ◽

Yoshinori Ishikawa ◽

Jessica B. Spinelli ◽

Haejin Yoon ◽

...

Keyword(s):

Small Molecule ◽

De Novo ◽

Nucleotide Synthesis ◽

Small Molecule Screen

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Small molecule screen for compounds that affect vascular development in the zebrafish retina

Mechanisms of Development ◽

10.1016/j.mod.2009.01.002 ◽

2009 ◽

Vol 126 (5-6) ◽

pp. 464-477 ◽

Cited By ~ 68

Author(s):

Satish S. Kitambi ◽

Kyle J. McCulloch ◽

Randall T. Peterson ◽

Jarema J. Malicki

Keyword(s):

Small Molecule ◽

Vascular Development ◽

Small Molecule Screen

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Discovery and Optimization of Selective Inhibitors of Meprin α (Part II)

10.20944/preprints202012.0383.v1 ◽

2020 ◽

Author(s):

Chao Wang ◽

Juan Diez ◽

Hajeung Park ◽

Christoph Becker-Pauly ◽

Gregg B. Fields ◽

...

Keyword(s):

Drug Discovery ◽

Small Molecules ◽

Small Molecule ◽

Hydroxamic Acid ◽

Therapeutic Potential ◽

Preceding Paper ◽

Close Relative ◽

Specific Inhibition ◽

Selective Inhibitors

Meprin α is a zinc metalloproteinase (metzincin) that has been implicated in multiple diseases, including fibrosis and cancers. It has proven difficult to find small molecules that are capable of selectively inhibiting meprin α, or its close relative meprin β, over numerous other metzincins which, if inhibited, would elicit unwanted effects. We recently identified possible molecular starting points for meprin α-specific inhibition through an HTS effort (see part I, preceding paper). In part II we report the optimization of a potent and selective hydroxamic acid meprin α inhibitor probe which may help define the therapeutic potential for small molecule meprin α inhibition and spur further drug discovery efforts in the area of zinc metalloproteinase inhibition.

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A small molecule screen identified N-Acetyl-L-cysteine for promoting ex vivo growth of single circulating tumor cells

10.1101/2020.08.19.257378 ◽

2020 ◽

Author(s):

Teng Teng ◽

Mohamed Kamal ◽

Oihana Iriondo ◽

Yonatan Amzaleg ◽

Chunqiao Luo ◽

...

Keyword(s):

Tumor Cells ◽

Circulating Tumor Cells ◽

Small Molecule ◽

Ex Vivo ◽

Single Cells ◽

Small Subset ◽

Blood Draw ◽

Small Molecule Screen ◽

Functional Analyses ◽

Single Ctcs

AbstractCirculating tumor cells (CTCs) can be isolated via a minimally invasive blood draw and are considered a “liquid biopsy” of their originating solid tumors. CTCs contain a small subset of metastatic precursors that can form metastases in secondary organs, and provide a resource to identify mechanisms underlying metastasis-initiating properties. Despite technological advancements that allow for highly sensitive approaches of detection and isolation, CTCs are very rare and often present as single cells, posing an extreme challenge for ex vivo expansion after isolation. Here, using previously established patient-derived CTC lines, we performed a small molecule drug screening to identify compounds that can improve ex vivo culture efficiency for single CTCs. We found that N-acetylcysteine (NAC) and other antioxidants can promote ex vivo expansion of single CTCs, by reducing oxidative and other stress particularly at the initial stage of single cell expansion. RNA-seq analysis of growing clones and non-growing clones confirmed the effect by NAC, but also indicate that NAC-induced decrease in oxidative stress is insufficient for promoting proliferation of a subset of cells with heterogeneous quiescent and senescent features. Despite the challenge in expanding all CTCs, NAC treatment lead to establishment of single CTC clones that have similar tumorigenic features, which will facilitate future functional analyses.

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Urea transporter proteins as targets for small-molecule diuretics

Nature Reviews Nephrology ◽

10.1038/nrneph.2014.219 ◽

2014 ◽

Vol 11 (2) ◽

pp. 113-123 ◽

Cited By ~ 21

Author(s):

Cristina Esteva-Font ◽

Marc O. Anderson ◽

Alan S. Verkman

Keyword(s):

Small Molecule ◽

Urea Transporter ◽

Transporter Proteins

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