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  • Jesus et al discovered a new series

    2023-01-28

    Jesus et al. discovered a new series of azaindole as Aurora inhibitors through various modification of GSK1070916 (47). They synthesized series from modification of the GSK1070916 and evaluated for in-vitro Aurora-B/INCENP and Aurora-A/TPX2 inhibition assays. Modified multidrug resistance transporter 48 and 49 showed IC50 value of 6.2 & 0.51 μM, respectively. Compound 49 was studied for cellular proliferation of A549 cells and showed EC50 value of 21 nM. Fluorescence activated cell sorting (FACS) analysis of compound 49 observed multipolar spindles disrupt at 12 nM and 37 nM in immune fluorescent microscopy. Proliferation of A549 cells were also constant with inhibition of Aurora-B in FACS analysis of 49, which exhibited the highest growth of 4N DNA polyploidy (30%), similar to GSK1070916. Spindle assembly analysis by immune-fluorescent microscopy showed disruption of multipolar spindles at 37 nM associated with Aurora-B inhibition and monopolar spindles phenotype associated with Aurora-A inhibition at 110 nM. Binding efficiency (BEI) of 49 was 25 [78], [79]. David et al. discovered orally bioavailable morpholine-based imidazo[1,2]pyrazine derivatives as Aurora kinase inhibitors and compound 50 was identified as most interesting profile molecules. Compound 50 displayed a phenotype which showed consistency with Aurora-A and Aurora-B kinase inhibition as pHH3 decreased phosphorylation and induced 4N DNA polyploidy. Moreover, compound 50 displayed potent inhibition of cell growth and survival with EC50 values of 19 and 20 nM, on Aurora-A and Aurora-B, respectively [80]. Zhong et al. discovered a series of potent 2-aminobenzimidazole based Aurora kinase inhibitors derived from SNS-314 (51). This series of compounds offered better aqueous solubility compared to their biaryl-urea analogues and sustained good activity profile in various enzymatic and in-vitro cell-based assays. SNS-314 showed activity against both Aurora-A and Aurora-B. Enzymatic assay was used for preliminary testing of initial set of benzimidazole derivative (52) exhibiting IC50 values of 17 nM & 5 nM on Aurora-A and Aurora-B, respectively [81]. Stefan et al. introduced di-heteroarylether series with lead scaffold 53 which resulted in excellent EC50/IC50 ratio on Aurora kinases; enzymatic IC50 values below 100 nM and cellular EC50 values between 60 and 800 nM. Best enzyme inhibition for this compound was detected on both, Aurora-A and Aurora-B [82]. Ignacio et al. worked on selectivity of the Aurora-A over Aurora-B. They established a structural source in a class of 2,4-dianilinopyrimidine inhibitors for Aurora-A selectivity. The equivalent residue in human kinases was aspartic acid or glutamic acid, which was near to 50%, while threonine was relatively rare about 6%. Compound 54 showed good correlation with docking data with IC50 of 0.01 and 1.9 μM on Aurora-A and Aurora-B, respectively on enzymatic assay. Cellular inhibition of the Aurora kinase determined 0.88 μM and 17 μM, respectively, on both kinase [83]. Rowson et al. synthesized a pentacyclic inhibitor (55) and found a potent Aurora-A and Aurora-B inhibitor with IC50 values of 4 and 5 nM, respectively. The co-crystal structure (PDB:3COH) of compound 55 revealed that methylpyrazole was placed at the back of the ATP pocket and the lactam part was extended towards solvent region. Aurora-A inhibition displayed that the pyrazole nitrogen and indole formed H-bonding interactions with Ala213, the amide backbone of the hinge region. Compound 55 showed high potency and good oral availability against tumor xenografts in mouse [84]. JNJ-7706621 (56) was reported by chan et al. which was a potent cell cycle inhibitor which targeted Aurora kinase and cyclin dependent kinases (CDK). This compound showed in-vitro enzymatic inhibition of Aurora-A and Aurora-B with IC50 of 11 nM and 4 nM, respectively which included inhibition of pHH3 and endoreduplication. The progression of cancer cells through G1 phase was delayed and arrested the cell cycle in G2/M phase [85].