Carbamoylphosphonates inhibit autotaxin and metastasis formation<i>in vivo</i>

Reich, Reuven; Hoffman, Amnon; Suresh, Raagini; Shai, Ofra; Frant, Julia; Maresca, Alfonso; Supuran, Claudiu T.; Breuer, Eli

doi:10.3109/14756366.2014.968146

Cited by 12 publications

(9 citation statements)

References 30 publications

(44 reference statements)

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“…CA II, IV, and XII) 48,81,82 . This approach was subsequently expanded to all classes of CAIs, such as among others to the dithiocarbamates (DTCs) [28][29][30]83 , xanthates 84 , carboxylates 31,41,85,86 , phosphonates [87][88][89][90][91][92] , and hydroxamates [93][94][95][96][97][98][99][100] , etc. X-Ray crystal structures are available for adducts of various isoforms (mainly hCA I and II) with all these classes of CAIs except the xanthates for which computational methods were used to assess their inhibition mechanism 30,83,88,100,101 .…”

Section: The Zinc Binders As Caismentioning

confidence: 99%

How many carbonic anhydrase inhibition mechanisms exist?

Supuran

2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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588

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Six genetic families of the enzyme carbonic anhydrase (CA, EC 4.2.1.1) were described to date. Inhibition of CAs has pharmacologic applications in the field of antiglaucoma, anticonvulsant, anticancer, and anti-infective agents. New classes of CA inhibitors (CAIs) were described in the last decade with enzyme inhibition mechanisms differing considerably from the classical inhibitors of the sulfonamide or anion type. Five different CA inhibition mechanisms are known: (i) the zinc binders coordinate to the catalytically crucial Zn(II) ion from the enzyme active site, with the metal in tetrahedral or trigonal bipyramidal geometries. Sulfonamides and their isosters, most anions, dithiocarbamates and their isosters, carboxylates, and hydroxamates bind in this way; (ii) inhibitors that anchor to the zinc-coordinated water molecule/hydroxide ion (phenols, carboxylates, polyamines, 2-thioxocoumarins, sulfocoumarins); (iii) inhibitors which occlude the entrance to the active site cavity (coumarins and their isosters), this binding site coinciding with that where CA activators bind; (iv) compounds which bind out of the active site cavity (a carboxylic acid derivative was seen to inhibit CA in this manner), and (v) compounds for which the inhibition mechanism is not known, among which the secondary/tertiary sulfonamides as well as imatinib/nilotinib are the most investigated examples. As CAIs are used clinically in many pathologies, with a sulfonamide inhibitor (SLC-0111) in Phase I clinical trials for the management of metastatic solid tumors, this review updates the recent findings in the field which may be useful for a structure-based drug design approach of more selective/potent modulators of the activity of these enzymes. KeywordsAnchoring to zinc-coordinated water, carbonic anhydrase, inhibition mechanism, inhibitors, occlusion of the active site entrance, out of the active site binding, zinc binder History

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Section: The Zinc Binders As Caismentioning

confidence: 99%

How many carbonic anhydrase inhibition mechanisms exist?

Supuran

2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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588

503

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“…Recently, a promising paper appeared on bisphosphonate based MMP‐CA inhibitors as a forerunner of possible drugs for bone cancer . A further development from our laboratory is a threefold inhibitor acting on the enzymes MMP‐CA‐ATX (autotaxin) based on a CPO .…”

Section: Discussionmentioning

confidence: 99%

Synthesis of Enantiomeric Aminoalkylcarbamoylphosphonates and Their Evaluation as Dual‐Action Anticancer MMP and Carbonic Anhydrase Inhibitors

Veerendhar

Cohen

Frant

et al. 2015

Heteroatom Chemistry

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Carbamoylphosphonates (CPOs) have recently been identified as extracellular in vivo active inhibitors of the cancer and metastasis‐promoting extracellular enzymes, carbonic anhydrases (CAs) IX and XII, and matrix metalloproteinase‐2 (MMP‐2). This article describes the stereoselective synthesis and the evaluation of the biological properties of a pair of enantiomeric aminoalkylcarbamoylphosphonates, which have been enantioselectively synthesized from l‐serine, using functional group‐transformations. The structures of the enantiomeric products have been determined by X‐ray crystallography. The enantiomeric purities of compounds have been confirmed by chiral shift reagent NMR experiments and by circular dichroism. In vitro evaluation of the CPOs synthesized revealed that they possess micromolar IC50 inhibitory action against CAIX and CAXII. The two enantiomers as well as the racemic or optically inactive ones do not differ by any significant extent from previously reported CPOs’ CA inhibitory values. On the other hand, MMPs inhibitory activities are rather weak; only MMP‐2 showed a notable IC50 value.

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“…Zinc-requiring ectoenzymes, which are defined here as secretory, membrane-bound, and organelle-resident enzymes, have attracted considerable attention because they play crucial roles in various physiological functions, and in a number of pathological processes, such as cancer progression, and metastasis [ 1 , 55 ]. Thus, they are regarded as potential therapeutic targets in the treatment of diseases [ 82 , 83 , 84 , 85 , 86 ]. Moreover, the activities of some zinc-requiring ectoenzymes, e.g., alkaline phosphatases (ALP), may be used as clinical markers to reflect systemic zinc status [ 87 , 88 ].…”

Section: Importance Of Znt Transporters In the Activation Of Ectoementioning

confidence: 99%

Understanding the Contribution of Zinc Transporters in the Function of the Early Secretory Pathway

Kambe

Matsunaga

Takeda

2017

IJMS

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More than one-third of newly synthesized proteins are targeted to the early secretory pathway, which is comprised of the endoplasmic reticulum (ER), Golgi apparatus, and other intermediate compartments. The early secretory pathway plays a key role in controlling the folding, assembly, maturation, modification, trafficking, and degradation of such proteins. A considerable proportion of the secretome requires zinc as an essential factor for its structural and catalytic functions, and recent findings reveal that zinc plays a pivotal role in the function of the early secretory pathway. Hence, a disruption of zinc homeostasis and metabolism involving the early secretory pathway will lead to pathway dysregulation, resulting in various defects, including an exacerbation of homeostatic ER stress. The accumulated evidence indicates that specific members of the family of Zn transporters (ZNTs) and Zrt- and Irt-like proteins (ZIPs), which operate in the early secretory pathway, play indispensable roles in maintaining zinc homeostasis by regulating the influx and efflux of zinc. In this review, the biological functions of these transporters are discussed, focusing on recent aspects of their roles. In particular, we discuss in depth how specific ZNT transporters are employed in the activation of zinc-requiring ectoenzymes. The means by which early secretory pathway functions are controlled by zinc, mediated by specific ZNT and ZIP transporters, are also subjects of this review.

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Carbamoylphosphonates inhibit autotaxin and metastasis formationin vivo

Cited by 12 publications

References 30 publications

How many carbonic anhydrase inhibition mechanisms exist?

How many carbonic anhydrase inhibition mechanisms exist?

Synthesis of Enantiomeric Aminoalkylcarbamoylphosphonates and Their Evaluation as Dual‐Action Anticancer MMP and Carbonic Anhydrase Inhibitors

Understanding the Contribution of Zinc Transporters in the Function of the Early Secretory Pathway

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