Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Molecules targeting mitosis, and specifically compounds targeting microtubule stability, are important in the treatment of cancer. Unfortunately, the mechanism of action of these agents can cause undesirable toxicities to healthy cells, inducing neurotoxicity and neutropenia in patients. In addition, many of these agents are subject to acquired resistance, usually through increased expression of membrane P-glycoprotein pumps. Due to the clinically proven utility of antimitotic therapeutics, the discovery of new agents with different mechanisms of action which may allow for the development of less toxic oncolytic treatments is highly desirable. This review describes key advances made over the last year toward the design and development of inhibitors of kinesin motor proteins, with particular emphasis placed on non-ATP-competitive, small-molecule inhibitors of kinesin spindle protein (Eg5).
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PMID:Inhibitors of kinesin motor proteins--research and clinical progress. 1602 79

Monastrol is the first characterised small molecule inhibitor of the motor protein Eg5 involved in bipolar mitotic spindle assembly. Eg5 localises to microtubules in mitosis, but not to interphase microtubules, suggesting that Eg5 inhibitors may be useful to specifically target proliferating tumour tissue, thereby avoiding dose-limiting neuropathy observed with other antimicrotubule agents like taxanes or vinca alkaloids. Because other antimicrotubule agents fail in multidrug resistance associated with P-glycoprotein (Pgp) over-expression, we investigated the interaction of monastrol with Pgp in vitro. By means of the calcein assay (with P388/dx cells and primary porcine brain capillary endothelial cells) and confocal laser-scanning microscopy (with L-MDR1 cells) we demonstrated that monastrol is a weak inhibitor of Pgp in vitro, with f2 values being about two orders of magnitude greater than those of the well-known inhibitors verapamil and quinidine. Monastrol also induces Pgp in vitro as measured by mRNA expression in LS180 cells after incubation with monastrol. However, its effect is weak compared to rifampicin. Whilst it reveals weak inhibitory and inductive characteristics, monastrol appears to be not transported by Pgp, as indicated by the lack of difference in the antiproliferative effect of this compound in cell lines with and without over-expression of Pgp. The observed interaction profile of monastrol with Pgp is promising for the development of other more potent Eg5 inhibitors.
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PMID:Interaction of the mitotic kinesin Eg5 inhibitor monastrol with P-glycoprotein. 1636 80

Human kinesin Eg5, which plays an essential role in mitosis by establishing the bipolar spindle, has proven to be an interesting drug target for the development of cancer chemotherapeutics. Here, we report the crystal structures of the Eg5 motor domain complexed with enastron, dimethylenastron, and fluorastrol. By comparing these structures to that of monastrol and mon-97, we identified the main reasons for increased potency of these new inhibitors, namely the better fit of the ligand to the allosteric binding site and the addition of fluorine atoms. We also noticed preferential binding of the S-enantiomer of enastron and dimethylenastron to Eg5, while the R-enantiomer of fluorastrol binds preferentially to Eg5. In addition, we performed a multidrug resistance (MDR) study in cell lines overexpressing P-glycoprotein (Pgp). We showed that one of these inhibitors may have the potential to overcome susceptibility to this efflux pump and hence overcome common resistance associated with tubulin-targeting drugs.
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PMID:Structural basis for inhibition of Eg5 by dihydropyrimidines: stereoselectivity of antimitotic inhibitors enastron, dimethylenastron and fluorastrol. 2059 85

The mitotic spindle is a validated target for cancer chemotherapy. Drugs such as taxanes and vinca alkaloids specifically target microtubules and cause the mitotic spindle to collapse. However, toxicity and resistance are problems associated with these drugs. Thus, alternative approaches to inhibiting the mitotic spindle are being pursued. These include targeting Eg5, a human kinesin involved in the formation of the bipolar spindle. We previously identified S-trityl-L-cysteine (STLC) as a potent allosteric inhibitor of Eg5. Here, we report the synthesis of a new series of STLC-like compounds with in vitro inhibition in the low nanomolar range. We also performed a multidrug resistance study in cell lines overexpressing P-glycoprotein and showed that some of these inhibitors may have the potential to overcome susceptibility to this efflux pump. Finally, we performed molecular docking of the compounds and determined the structures of two Eg5-inhibitor complexes to explain the structure-activity relationship of these compounds.
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PMID:Structure-activity relationship and multidrug resistance study of new S-trityl-L-cysteine derivatives as inhibitors of Eg5. 2134 20