Matthew et al synthesized and carried out SAR

Matthew et al. synthesized and carried out SAR studies of imidazo-[1,2-a]-pyrazine as Aurora kinase inhibitors with enhanced kinase selectivity and found that psoralen 39 showed optimal potency on Aurora-A and Aurora-B with IC50 value of 4 nM and 13 nM while on phosphorylation histone H3 (pHH3), EC50 was 62 nM. Pyridine nitrogen formed H-bonding with Phe144. This interaction moved the glycine rich loop about 1.5 Å closer to the inhibitor in the X-ray structure of 39 (PDB: 3VAP). It maintained a H-bond with Asp274, at the DFG loop and was pushed out by approximately 1 Å to accommodate the increased bulk of the acetamides [71]. Jean et al. evaluated 1,6-disubstituted-1H-pyrazolo[3,4-d]pyrimidines as Aurora kinase inhibitor and reported compound 40 with good selectivity profile over different kinase panel with IC50 value of 1–5 μM. Aurora-A and Aurora-B phosphorylation levels were checked on K-562 and found inhibition at IC50 of 0.004 μM and 0.06 μM, respectively. The docking study showed interaction with ATP binding site of Aurora-A. Pyrazolopyrimidine side bound to hinge region with two H-bonds and 2-methoxymethyl-pyrrolidine amide moiety joined in an optimal manner with the side-chains of Arg220 and Arg137 of Aurora-A. Results of in-vivo HCT-116 nude mouse xenograft model showed that compound 40 inhibited the tumor growth by 30–40%. Few animals in this study died which indicated that 40 was not tolerated at this regimen of dosing [72]. Angela et al. prepared new imidazo[1,2]pyrazine with good oral bioavaibility of compounds. From various synthesized molecules, compound 41 showed excellent activity over in-vitro and in-vivo profile. It held inhibition at 4 nM and 13 nM in Aurora-A and Aurora-B, respectively in-vitro. In cancer cell lines, compound 41 inhibited pHH3 at ser10 which confirmed inhibition of Aurora-B kinase with IC50 value of 63 nM. From these data, compound 41 was further screened for in-vivo bioavaibility on rat and found AUC of 4.73 μM in Pharmacokinetic (Pk) profile. Compound 41 was used for pharmacodynamic marker in pHH3 in-vivo. A single dose of compound 41 at 100 mg/kg was given to A2780 xenografts grown in nude mice resulted in inhibition of the biomarker (Histone H3 phosphorylation) by 83% after 2 h [73]. Zhaoyang et al. synthesized thiazole and thiophene derivatives as potent Aurora-A and Aurora-B inhibitors. Most potent compound 42 showed activity on Aurora-A and Aurora-B with IC50 value of 4 nM and 13 nM, respective and pHH3 EC50 was 377 nM which indicated excellent inhibitory activity [74]. Tao et al. prepared injectable imidazo-[1,2-a]pyrazine core as Aurora kinases inhibitors. Compound SCH 1473759 (43) was reported as highest active compound with IC50 values of 11 nM and 29 nM on Aurora-A and Aurora-B, respectively. This compound showed high intrinsic aqueous solubility with 11 mM. Temperature dependent fluorescence (TdF) study showed that compound 43 directly bound to kinase domain of Aurora-A and Aurora-B and was confirmed with Kd values of 0.02 nM and 0.03 nM, respectively. Compound 43 was given at a dose of 10 mg/kg (ip, bid) in A2780 human tumor model in mouse which reduced tumor size with 69%TGI at day 16. In the lower dose of 5 mg/kg (ip, bid), it expressed 50% TGI on day 16 [75]. Chao-Cheng et al. synthesized and studied pharmacological profile of pyrrole-indolin-2-one series for Aurora kinases inhibition. Potent compound 44 selectively inhibited Aurora-A over Aurora-B with IC50 values of 12 nM and 156 nM, respectively. Compound 45 was ethyl ester analogue of 44. In western blot analysis, it blocked the phosphorylation of Aurora-A and Aurora-B. Replacement of the carboxyl group with an amino group lost activity for Aurora-A with IC50 of 2.19 μM and retained the activity for Aurora-B [76]. Stephanie et al. designed and synthesized alkenyl indazole series with strong inhibition of both, Aurora-A and Aurora-B. Their study concluded in the discovery of compound 46 with potent Aurora-B activity and it was 20 times more over Aurora-A. Compound 46 exhibited IC50 values of 1.9 nM & 0.099 μM, respectively. Binding sites of X-ray crystal structures of Aurora-A and Aurora-B showed difference by two residues only. Phe172 and Glu177 amino acid residues of Aurora-B differed with Tyr212 and Thr217 residues of Aurora-A [77].