Insights on Cancer Cell Inhibition, Subcellular Activities, and Kinase Profile of Phenylacetamides Pending 1H-Imidazol-5-One Variants

Abstract

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.

Exploring antiproliferative activities and kinase profile of ortho‐substituted N‐(4‐(2‐(benzylamino)‐2‐oxoethyl)phenyl)benzamides

“…Compound 4 was the only compound that affected, with varying degrees of specificity, most of the members of the SFK, with Yes and Hck ranking 1st and 8th, respectively (Table 2). While KAC‐12 did not show any specificity toward the affected tyrosine kinases (Omar et al., 2022), KIM‐161 had certain specificity towards the BRK family member, Srm (Khayat et al., 2022).…”

“…KIM‐161 was another KX‐01‐based inhibitor with an IC 50 of 0.29 μM on the human colon cancer cell line, HCT116. Its 1 H ‐imidazol‐5‐one moiety allowed it to primarily affect Srm and JAK1 as well as completely shut down phospho‐Akt1/2/3 and phospho‐Erk1/2 (Khayat et al., 2022). Embarking on this concept, we postulated that another shifting of cellular kinase profile will likely occur when the outer ring of the scaffold N ‐benzyl‐4‐(benzoylamino)phenylacetamide is decorated with a bulky substitution at the ortho ‐position (Figure 1).…”

Multifaceted Anticancer Potential of Gnidia glauca (Fresen.) Gilg Leaf Alkaloids: Impact on Multiple Cellular Targets

“…A 96-well microplate reader was used to measure each well’s absorbance at 340 nm after incubation. Data were plotted, and tubulin polymerization in several wells was contrasted …”

“…Data were plotted, and tubulin polymerization in several wells was contrasted. 15 4.9. Mitochondrial Membrane Potential (JC-1) Assay.…”

The Relationships of AMPK Allosteric Inhibitors with Their Activities against Breast Cancer in 2D and 3D Models

“…To address our concerns we tested compounds MAK-1 and MAK-6 in a battery of in vitro ADME assays, which included maximum kinetic aqueous solubility in 2 % DMSO/phosphatebuffered saline (PBS), stability in mouse and human liver microsomes in the presence and absence of nicotinamide adenine di-nucleotide phosphate (NADPH), inhibitory activity against the three major human cytochrome P450 metabolizing enzymes (CYP3A4, CYP2D6 and CYP2C9), stability in mouse plasma at 37 °C and plasma protein binding (expressed as percent bound to mouse plasma protein at 37 °C). [20,31] The results are summarized in Table 2. Note that MAK-11 was not included in this study because it was synthesized later after this stage because we casually perform this profiling at early stages on any discovery project.…”