The Discovery of PLK4 Inhibitors: (E)-3-((1H-Indazol-6-yl)methylene)indolin-2-ones as Novel Antiproliferative Agents
ABSTRACT 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.
- SourceAvailable from: Zhiqiang Yu
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- "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 . "
ABSTRACT: The identification of novel anticancer agents with high efficacy and low toxicity has always been an intriguing topic in medicinal chemistry. The unique structural features of spirooxindoles together with diverse biological activities have made them promising structures in new drug discovery. Among spirooxindoles, CFI-400945 holds its promise as the first potent PLK4 inhibitor, the fumarate of CFI-400945 has entered phase I clinical trials for the treatment of solid tumors. However, questions remain as to whether PLK4 is the only relevant therapeutic target for CFI-400945. To highlight this significant progress of CFI-400945 in last two years, this review centers on the identification from a focused kinase library, structural optimizations and strategies involved, structure-activity relationships, modes of action, target validation, chemical synthesis and, more importantly, the kinase selectivity between PLK4 and other targets. Copyright © 2015 Elsevier Masson SAS. All rights reserved.European Journal of Medicinal Chemistry 03/2015; 95. DOI:10.1016/j.ejmech.2015.03.020 · 3.43 Impact Factor
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- "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. "
ABSTRACT: A hybrid pharmacophore approach was adopted to design and synthesize new series of isatin-pyridine hybrids. All the newly prepared hybrids (5a-o, 8 and 11a-d) were in vitro evaluated for their anti-proliferative activity against three human cancer cell lines, namely HepG2 hepatocellular carcinoma, A549 lung cancer and MCF-7 breast cancer. Compound 8 emerged as the most active member against HepG2 cell line (IC50 = 2.5 ± 0.39 μM), with 2.7-fold increased activity than the reference drug, doxorubicin (IC50 = 6.9 ± 2.05 μM). Whilst, compound 11c was found to be the most potent counterpart against A549 and MCF-7 cell lines with IC50 values of 10.8 ± 1.15 and 6.3 ± 0.79, respectively. The weightiness of the utilization of non-cleavable linker, as the chalcone linker, and simplification of the first group, was explored via the SAR study. Furthermore, a QSAR model was built to explore the structural requirements controlling the cytotoxic activities. Notably, the predicted activities by the QSAR model were very close to those experimentally observed, hinting that this model could be safely applied for prediction of more efficacious hits comprising the same skeletal framework. Finally, a theoretical kinetic study was established to predict the ADME of the active hybrids. Copyright © 2014 Elsevier Masson SAS. All rights reserved.European Journal of Medicinal Chemistry 12/2014; 90C:684-694. DOI:10.1016/j.ejmech.2014.12.010 · 3.43 Impact Factor
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ABSTRACT: The Nek2 and Plk4 kinases serve as crucial regulators of mitotic processes such as the centrosome duplication cycle and spindle assembly. Deregulation of these processes can trigger chromosome instability and aneuploidy, which are hallmarks of many solid tumors, including breast cancer. Emerging data from the literature illustrated various functions of Nek2 in breast cancer models, with compelling evidence of its prognostic value in breast tumors. The two kinases control distinct steps in the centrosome-centriole cycle and their dysregulation lead to centrosome amplification, marked by the presence of more than two centrosomes within the cell. We found single or composite overexpression of these kinases in breast tumor samples, regardless of subtype, which strongly associated with poor prognosis. Interestingly, in a panel of established cell lines, both kinases are highly expressed in Her2-positive breast cancer cells exhibiting centrosome amplification and trastuzumab resistance. In summary, it appears that Nek2 and Plk4 might synergize to promote breast tumorigenesis and may also be involved in tamoxifen and trastuzumab resistance.Frontiers in Bioscience 01/2014; 19(2):352-65. DOI:10.2741/4212 · 4.25 Impact Factor