Aqueous solubility of kinase inhibitors: I the effect of hydrophilic polymers on their γ-cyclodextrin solubilization

2020 ◽  
Vol 55 ◽  
pp. 101462 ◽  
Author(s):  
Pitsiree Praphanwittaya ◽  
Phennapha Saokham ◽  
Phatsawee Jansook ◽  
Thorsteinn Loftsson
2022 ◽  
Vol 12 ◽  
Author(s):  
Maan T. Khayat ◽  
Abdelsattar M. Omar ◽  
Farid Ahmed ◽  
Mohammad I. Khan ◽  
Sara M. Ibrahim ◽  
...  

Structural changes of small-molecule drugs may bring interesting biological properties, especially in the field of kinase inhibitors. We sought to study tirbanibulin, a first-in-class dual Src kinase (non-ATP competitive)/tubulin inhibitor because there was not enough reporting about its structure–activity relationships (SARs). In particular, the present research is based on the replacement of the outer ring of the biphenyl system of 2-[(1,1′-biphenyl)-4-yl]-N-benzylacetamide, the identified pharmacophore of KX chemotype, with a heterocyclic ring. The newly synthesized compounds showed a range of activities in cell-based anticancer assays, agreeing with a clear SAR profile. The most potent compound, (Z)-N-benzyl-4-[4-(4-methoxybenzylidene)-2-methyl-5-oxo-4,5-dihydro-1H-imidazol-1-yl]phenylacetamide (KIM-161), demonstrated cytotoxic IC50 values at 294 and 362 nM against HCT116 colon cancer and HL60 leukemia cell lines, respectively. Profiling of this compound (aqueous solubility, liver microsomal stability, cytochrome P450 inhibition, reactivity with reduced glutathione, and plasma protein binding) confirmed its adequate drug-like properties. Mechanistic studies revealed that this compound does not depend on tubulin or Src kinase inhibition as a factor in forcing HL60 to exit its cell cycle and undergo apoptosis. Instead, KIM-161 downregulated several other kinases such as members of BRK, FLT, and JAK families. It also strongly suppresses signals of ERK1/2, GSK-3α/β, HSP27, and STAT2, while it downregulated AMPKα1 phosphorylation within the HL60 cells. Collectively, these results suggest that phenylacetamide-1H-imidazol-5-one (KIM-161) could be a promising lead compound for further clinical anticancer drug development.


Author(s):  
Maryam Faraj Pour Mojdehi ◽  
Mokhtar Ganjali Koli ◽  
Mahsa Dolatkhah Ouch Bolagh ◽  
Mina Ghane Gardeh ◽  
Seyed Majid Hashemianzadeh

It is well known that the limited aqueous solubility of some drugs often reduces their bioavailability to targets.


2017 ◽  
Vol 27 (2) ◽  
pp. 187-190 ◽  
Author(s):  
Jackie D. Kendall ◽  
Anna C. Giddens ◽  
Kit Yee Tsang ◽  
Elaine S. Marshall ◽  
Claire L. Lill ◽  
...  

Planta Medica ◽  
2008 ◽  
Vol 74 (09) ◽  
Author(s):  
V Myrianthopoulos ◽  
P Magiatis ◽  
AL Skaltsounis ◽  
L Meijer ◽  
E Mikros

2009 ◽  
Vol 47 (05) ◽  
Author(s):  
G Kéri ◽  
L Őrfi ◽  
Z Greff ◽  
Z Varga ◽  
B Szokol ◽  
...  

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