Determination of intestinal permeability of rigosertib (ON 01910.Na, Estybon): correlation with systemic exposure

White, Michael P.; Babayeva, Mariana; Taft, David R.; Maniar, Manoj

doi:10.1111/jphp.12057

Cited by 3 publications

(2 citation statements)

References 34 publications

(54 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Oral bioavailability, i.e., the quantity of drug reaching the blood circulation, depends on different factors, the two most important being presystemic metabolism (intestinal and hepatic) and intestinal drug transport (Yeo et al, 2011;Li et al, 2012;Zhang et al, 2012;White et al, 2013;Hierro et al, 2014). Presystemic metabolism is primarily associated with intestinal and liver P450, whereas drug extrusion and import are mediated by several membrane proteins (transporters).…”

Section: Pharmacokinetic Studymentioning

confidence: 98%

Comparative pharmacokinetics of the main compounds of Shanzhuyu extract after oral administration in normal and chronic kidney disease rats

Zhao

Qian

Shang

et al. 2015

Journal of Ethnopharmacology

View full text Add to dashboard Cite

Section: Pharmacokinetic Studymentioning

confidence: 98%

Comparative pharmacokinetics of the main compounds of Shanzhuyu extract after oral administration in normal and chronic kidney disease rats

Zhao

Qian

Shang

et al. 2015

Journal of Ethnopharmacology

View full text Add to dashboard Cite

“…Both Polo-like kinase (PLK) and Aurora kinases have been suggested as targets for the treatment of brain cancers. , Among the PLK1 inhibitors that have advanced to the clinic (Table ), volasertib ( 99 ), BI 2536 ( 100 ), GSK 461364 ( 101 ), rigosertib ( 102 ), and NMS-P937 ( 103 ) have been shown to be substrates of P-gp, and therefore, CNS penetration is expected to be limited.…”

Section: Plk1/aurora Kinasesmentioning

confidence: 99%

Small Molecule Kinase Inhibitors for the Treatment of Brain Cancer

Heffron¹

2016

J. Med. Chem.

112

186

View full text Add to dashboard Cite

In addition to each of the factors that govern the identification of a successful oncology drug candidate, drug discovery aimed at treating neurological cancer must also consider the presence of the blood-brain barrier (BBB). The high level of expression of efflux transporters (e.g., P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp)) at the BBB limits many small molecules from freely reaching the brain, where neurooncologic malignancies reside. Furthermore, many of the targets identified for the potential treatment of central nervous system (CNS) malignancies suggest that kinase inhibitors, capable of penetrating the BBB to reach their target, would be desirable. This Perspective discusses the unmet need for neurooncology treatments, the appeal of kinase targets in this space, and a summary of what is known about free brain penetration of clinical inhibitors of kinases that are of interest for the treatment of brain cancer.

show abstract

Exploring Novel PLK1 Inhibitors based on Computational Studies of 2,4-Diarylaminopyrimidine Derivatives

Yang

Zhao

Zheng

et al. 2024

LDDD

View full text Add to dashboard Cite

Background: Polo-like kinase 1 (PLK1) is an important target for anti-cancer drugs. A series of novel 2,4-diarylaminopyrimidine derivatives (DAPDs) as PLK1 inhibitors (PLKIs) with remarkable activities have been reported recently. Methods: A systemically computational study was performed on these DAPDs, including three-dimensional quantitative structure-activity relationship (3D-QSAR) modeling, molecular docking, and molecular dynamics (MD) simulation. Results: The constructed 3D-QSAR models exhibited reliable predictability with satisfactory validation parameters. The dockings revealed the binding modes of DAPDs in PLK1 protein, and two key residue, Cys133 and Phe183, could interact with DAPDs by hydrogen bonds and π-π stacking, which might be significant for the activity of these PLKIs. Eight compounds with higher predicted activity than the most active DAPD-compounds (16) were designed based on the 3D-QSAR models. These newly designed compounds also exhibited higher docking scores than compound 16 in the binding pocket of PLK1. The ADME predictions and MD simulations further indicated that two hit compounds with reasonable pharmacokinetics properties could stably bind with PLK1 and have the potential to become novel PLKIs. Conclusion: Two newly designed compounds might have the potential to be novel PLKIs. These results might provide important information for the design and development of novel PLKIs.

show abstract

Determination of intestinal permeability of rigosertib (ON 01910.Na, Estybon): correlation with systemic exposure

Abstract: The results of this research indicated that rigosertib is a promising candidate for oral delivery. Further studies are needed to evaluate the potential impact of P-gp and other intestinal transporters on the oral absorption of this promising anticancer agent.

Cited by 3 publications

References 34 publications

Comparative pharmacokinetics of the main compounds of Shanzhuyu extract after oral administration in normal and chronic kidney disease rats

Comparative pharmacokinetics of the main compounds of Shanzhuyu extract after oral administration in normal and chronic kidney disease rats

Small Molecule Kinase Inhibitors for the Treatment of Brain Cancer

Exploring Novel PLK1 Inhibitors based on Computational Studies of 2,4-Diarylaminopyrimidine Derivatives

Contact Info

Product

Resources

About