The family of Polo-like Kinases is important in the regulation of mitotic progression; this work keys on one member, namely Polo-like Kinase 4 (PLK4). PLK4 has been identified as a candidate anti-cancer target which prompted a search for potent and selective inhibitors of PLK4. The body of the paper describes lead generation and optimization work which yielded nanomolar PLK4 inhibitors. Lead generation began with directed virtual screening, using a ligand based focused library and a PLK4 homology model. Validated hits were used as starting points for the design and discovery of PLK4 inhibitors of novel structure, namely (E)-3-((1H-indazol-6-yl)methylene)indolin-2-ones. Computational models, based on a published X-ray structure (PLK4 kinase domain), were used to understand and optimize the in vitro activity of the series; potent anti-proliferative activity was obtained. The kinase selectivity profile and cell cycle analysis of selected inhibitors are described. The results of a xenograft study with an optimized compound 50 (designated CFI-400437) support the potential of these novel PLK4 inhibitors for cancer therapy.
"Although these molecules such as indolinone 15 showed potent PLK4 inhibition, antiproliferative activity and robust tumor inhibition , some drawbacks were also observed in these inhibitors, namely the strong inhibition of CYP450, low pharmacokinetic properties (low oral exposure particularly) and configurational lability  . So the key questions are to further improve the drug-like properties of these inhibitors through rational modifications . "
European Journal of Medicinal Chemistry 03/2015; 95. DOI:10.1016/j.ejmech.2015.03.020 · 3.45 Impact Factor
"Therefore, in order to investigate the influence of structural modifications on the biological activity of compound 1, we synthesised a small library of (3Z)-3-(2-[4-(aryl)-1,3-thiazol-2-yl]hydrazin-1- ylidene)-2,3-dihydro-1H-indol-2-ones. As in the original compound 1, we have conserved the indolinone and thiazole moieties that have been reported as important fragments in a number of bioactive molecules, such as selective chymase inhibitors , polo-like kinase 4 (PLK4) inhibitors , Beta-secretase 1 (BACE1) inhibitors , chemoattractant receptorhomologous molecule expressed on Th2 cells (D2 prostanoid receptor ) (CRTH2 (DP2)) antagonists , MAO inhibitors  antimycobacterial [28,29], anti-Candida , and antimicrobial . "
"The FDA approval of sunitinib paved the way to design and synthesis of various isatin-based molecules with diverse activities against cancer . In this context, many synthetic isatin-based derivatives were developed to inhibit diverse tyrosine and serine/threonine kinases, to name just a few, c-Met kinase , c-Src kinase , RET kinase , FLT3 kinase , cyclin-dependent kinases (CDKs) , glycogen synthase kinase 3b (GSK-3b) , Aurora B kinase , p38a MAP kinase , JNK3 MAP kinase , p90 ribosomal S6 protein kinase 2 (RSK2)  and Polo-like kinase 4 (PLK4)  . Over the last decade, numerous studies pointed out the importance of isatin based anticancer hybrids as promising chemotherapeutic agents. "
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