Discovery of 4-Aryl-N-arylcarbonyl-2-aminothiazoles as Hec1/Nek2 Inhibitors. Part I: Optimization of in Vitro Potencies and Pharmacokinetic Properties

Abstract

A series of 4-aryl-N-arylcarbonyl-2-aminothiazoles of scaffold 4 was designed and synthesized as Hec1/Nek2 inhibitors. Structural optimization of 4 led to compound 32 bearing C-4' 4-methoxyphenoxy and 4-(o-fluoropyridyl)carbonyl groups that showed low nanomolar in vitro antiproliferative activity (IC50: 16.3-42.7 nM), high intravenous AUC (64.9 μM·h, 2.0 mg/kg) in SD rats, and significant in vivo antitumor activity (T/C = 32%, 20 mg/kg, IV) in mice bearing human MDA-MB-231 xenografts. Cell responses resulting from Hec1/Nek2 inhibition were observed in cells treated with 32, including a reduced level of Hec1 coimmunoprecipitated with Nek2, degradation of Nek2, mitotic abnormalities, and apoptosis. Compound 32 showed selectivity toward cancer cells over normal phenotype cells and was inactive in a [(3)H]astemizole competitive binding assay for hERG liability screening. Therefore, 32 is as a good lead toward the discovery of a preclinical candidate targeting Hec1/Nek2 interaction.

NEK2 Is an Effective Target for Cancer Therapy With Potential to Induce Regression of Multiple Human Malignancies

“…A 4-aryl-N-arylcarbonyl-2aminothiazole was designed and synthesized as an HEC1/ NEK2 inhibitor. This compound also demonstrated inhibition of tumor growth in a xenograft breast cancer model (71).…”

Synthesis, Biological Evaluation, and Molecular Docking of Novel Thiazoles and [1,3,4]Thiadiazoles Incorporating Sulfonamide Group as DHFR Inhibitors

“…Of these privileged candidates in drug discovery are the thiazoles and thiadiazoles which have been identified to play a necessary role in medicinal chemistry. Thiazoles with (NH) or (N=C) group at position 2 are associated with a broad spectrum of biological properties including anticancer, anticonvulsant, antidiabetic, anti‐inflammatory, and antimicrobial activities. Recently, they can be used as antileishmanial and neuroprotective agents.…”

Design, Synthesis, and Anticancer Activities of Novel 2-Amino-4-phenylthiazole Scaffold Containing Amide Moieties

“…e 2-aminothiazole scaffold has played an important role in medicinal chemistry and drug discovery research. e derivatives of 2-aminothiazole are recognized by a wide range of pharmacological activities, including anticancer [1][2][3], anticonvulsant [4,5], antidiabetic [6,7], antihypertensive [8], anti-inflammatory [9,10], antiviral [11], antimicrobial [12,13], and antileishmanial [14] activities and neuroprotective agents [8]. Numerous drugs and active compounds ( Figure 1) containing 2-aminothiazole or 2-amino-4-phenylthiazole scaffold have been exhibiting a wide range of strong antitumor activities.…”

“…Numerous drugs and active compounds ( Figure 1) containing 2-aminothiazole or 2-amino-4-phenylthiazole scaffold have been exhibiting a wide range of strong antitumor activities. Compound 1 showed low nanomolar in vitro antitumor activity and selectivity toward cancer cells over normal phenotype cells, which were identified as Hec1/Nek2 inhibitor [3]. Compound 2 (CYC-116, Cyclacel) was an effective Aurora A/B inhibitor and a slightly weaker inhibitor of VEGFR2 and was currently in Phase I clinical trials [15,16].…”