Ryoichi et al modified potent clinical candidate VX with cya
Ryoichi et al. modified potent clinical candidate VX-680 (6) with 3-cyano-6-(5-methyl-3-pyrazolamino)pyridine as Aurora kinase inhibitor. Substituted cyano pyridine derivative (7) inhibited proliferation of HCT-116 cells with an IC50 value of 115 nM. It showed tumor inhibition in mice model at a dose of 30 mg/kg without decrease in body weight. It also showed enzymatic Aurora-A and Aurora-B kinases inhibition in-vitro with Ki values of 1.2 nM and 101 nM, respectively . Mohane et al. identified furo[2,3-d]pyrimidine derivatives as Aurora-A inhibitors. Among them, 5z 8 was the highest active compound of the series displaying good binding interactions. In-vitro enzymatic assay of compound 8 on Aurora-A showed IC50 value of 0.309 μM. Co-crystalized structure (PDB: 3M11) analysis data of Aurora-A with compound 8 showed formation of two H-bonds at hinge region and one H-bond with Lys162. Phenyl urea substituent fully occupied the binding pocket . Rong-geng et al. designed, synthesized and evaluated novel fused benzimidazole derivatives as Aurora-A inhibitors using structural features from existing molecules. Compound 9 showed cytotoxicity effect against HCT-116 cell line with IC50 of 8.71 μM and showed significant inhibition of Aurora-A with IC50 of 7.58 μM. This data were important for lead optimization and development of compound 9 as drug candidate . Nathalie et al. designed and synthesized potent imidazo[1,2-a]pyrazine derivatives as Aurora-A inhibitors and co-crystallization of compound 10 demonstrated up to 70 times greater selectivity in cell-based Aurora kinase pharmacodynamics biomarker assay. Compound 10 inhibited recombinant human Aurora-A with IC50 value of 0.060 μM. In cells, compound 10 inhibited Aurora-A and Aurora-B with cellular IC50 values of 0.15 and 10.54 μM, respectively. X-ray crystallography study revealed that compound 10 bound to Aurora-A (PDB: 2XNE) at the ATP binding site and formed H-bond with Ala213 of hinge region. Scaffold of the compound buried under hydrophobic pocket containing Lue263. Different conformation of the sulphonamide group of compound 10 formed H-bond with Thr217. The HCT-116 cell growth inhibition of compound 10 investigated with GI50 value of 2.4 μM . Simona et al. reported the thieno[3,2-c]pyrazole derivatives as Aurora-A kinase inhibitors. Most potent lead reported was compound 11 which was effective in-vivo in HL-60 tumor model and was able to induce significant tumor growth inhibition (TGI). It showed Aurora-A kinase inhibition with IC50 value of 18 nM. It also showed inhibition of pHH3 after treatment in HCT-116 cell line. Compound 11 revealed interaction under the glycine-rich loop with phenyl group. Terminal ethyl group of compound 11 was directed towards the main chain amino acids, Glu260 and Asn261, at the bottom of the pocket. Furthermore, this ethyl moiety was placed in a cavity which was oriented towards Leu263 and extended towards the side chain residues like Glu260, Asn261 and Asp274 (PDB: 2XRU) . Mohane et al. proved novel pyrazole derivative (12) as Aurora-A kinase inhibitor with IC50 value of 15.1 μM using structure based virtual screening method. Ethyl carboxylate side chain of compound 12 bound with Aurora-A which improved its potency and was identified by crystallography study of the complex. Bio-isosteric replacement of ester with amide linkage (ethyl to 3-acetamidophenyl ring) led to the generation of compound 13 having 450-fold improved Aurora-A kinase inhibition with IC50 value of 33 nM as compared to 12. Compound 13 showed selective inhibition due to change in confirmation of Aurora-A and formation of H-bond of 3-acetamide group with non-conserved Thr217. Imine nitrogen also interacted with back bone of hinge region amino acid Ala213 (PDB:3FDN) . Mohane et al. performed molecular design studies of Aurora-A inhibitors using SAR, virtual screening and docking. Synthesis of compound 14 revealed important H-bond interactions between tricyclic core and hinge, with IC50 value of 15.1 μM. In optimization process, it was found that compound 14 showed important interactions with Leu139, Gly216, and Leu263 .