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 anticancer 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 antiproliferative 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.

Design, synthesis and QSAR study of certain isatin-pyridine hybrids as potential anti-proliferative agents

“…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 [10], c-Src kinase [11], RET kinase [12], FLT3 kinase [13], cyclin-dependent kinases (CDKs) [14], glycogen synthase kinase 3β (GSK-3β) [15], Aurora B kinase [16], p38α MAP kinase [17], JNK3 MAP kinase [18], p90 ribosomal S6 protein kinase 2 (RSK2) [19] and Polo-like kinase 4 (PLK4) [20,21].…”

Effective Laboratory-Scale Preparation of Axitinib by Two CuI-Catalyzed Coupling Reactions

“…Compound 3 (426 g, 1.6 mol, 1.0 equiv) react with 2,3-dihydropyran (DHP, 672 g, 8.0 mol, 5equiv) in tetrahydrofuran (4.5 L) in the presence of methanesulfonic acid (24 g, 0.24 mol, 0.15 equiv), the mixture refluxing for 6 hours to complete the reaction detected by HPLC. The mixture is concentrated, neutralized using Na 2 CO 3 aqueous solution (100 g in 1L water) and filtered to obtain (E)-6-nitro-3- 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 The raw product can be refined by slurring with water and filtering through a short silica gel column to provide a product with purity above 99 % by HPLC.…”

Polo-like Kinase 1 as a Target for Anti-tumor Therapy

“…Na buněčných liniích nádoru prsu bylo rovněž ukázáno, že deplece Plk4 snižuje jejich proliferaci ve srovnání s buňkami normální tkáně [12]. Byla také vyvinuta řada inhibitorů Plk4, které ukázaly protinádo-rový efekt na buněčných a in vivo modelech nádoru prsu [13].…”