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  • Fencilli et al reported derivatives of PHA

    2024-04-01

    Fencilli et al. reported derivatives of PHA-680626 (15) which demonstrated strong anti-proliferative activity against large group of leukaemia cell lines including IM-resistant BAF3 cells expressing mutants like T315I, M351T and E255K. Decrease in Histone H3 phosphorylation led to induction of endo-reduplication followed by polyploid cells accumulation. Substitution at the pro- R position of the benzylic methylene with methoxy group leads to synthesis of PHA-739358 (16). In cell lines with origins from different human tumor types, it showed inhibition of Aurora-A competitive with ATP with an IC50 of 13 nM. In-vitro anti-proliferative activity in various cell lines showed IC50 values in range from 28 to 140 nM. Aurora-A crystal structure with compound 16 revealed direction of benzyl group was crowded around Leu263. Scaffold of the derivative interacted with hinge region amino Autophagy Compound Library Ala213 (PDB:2J50, 2V7A) [43], [44], [45]. Mudongo et al. reported that Aurora kinase is important target Autophagy Compound Library in the treatment of cancer and compound 17 with a tricyclic ring system was recognized as a favourable scaffold for binding Aurora-A for inhibition. Introducing 2-methoxy benzyl group at the 6-position of the pyrrolidone ring and furan ring at the 2-position of the pyrazole moiety led to potent activity. IC50 of compound 17 for Aurora-A was found to be 560 nM. Molecular modelling studies revealed important H-bonding interactions of tricyclic core with the hinge region Glu211 and Ala213 [46]. Carpeneli et al. studied compound 18 which was designed to interact with ATP-binding pockets. Cyclopropylamide moiety was attached near to the solvent binding region of the ATP pocket. Crystal of Aurora-A with compound 18 complex showed that Aln213 of the hinge region of Aurora-A bound to the compound with two H-bonds. It was selective Aurora -A inhibitor with an IC50 value of 42 nM [47]. Warner et al. studied the purine base of ATP, bound to Aurora-A, and 4-amino-N-(2-pyrimidinyl)-benzensulfonamide fragment. They designed 6,7-dimethoxypyrimido[4,5-b]indolinone moiety and in docking studies, it showed similar orientation of the phosphate group of the ATP binding. Synthesized compound 19 was proved potent selective compound and active against Aurora-A kinase having an IC50 value of 94 nM. The selectivity of this compound was presumed by the H-bonding between Lys143 and oxygen of sulfone moiety (PDB: 2NP8). Other kinases of serine/threonine family don't have Lys143 [48], [49]. Morarity et al. prepared series of 2-amino-pyrrolo[2,3-d]pyrimidines and evaluated for Aurora-A kinase inhibitor activity. Compound 20 from this series showed in-vitro Aurora-A enzyme assay inhibition with IC50 of 0.8 nM. It was potent against human cell lines. It caused polyploidy in H460 by inhibiting pHH3. It was presumed that H-bonding at ATP binding site was formed between the inhibitor and the enzyme [49], [50]. Mortlock et al. prepared series of quinazoline derivatives and filed patent on potent derivatives as Aurora kinase inhibitors. Compound 21 was found active on various kinases. It was ATP-competitive inhibitor and act on Aurora kinase with mechanism causing irregular mitosis. Aurora-A inhibition was found 60% as compared to other standard Aurora kinase inhibitors. Accumulation of multinucleated cells led to apoptosis. In-vitro inhibition of both Aurora-A and Aurora-B prevented proliferation of MCF-7 human breast cancer cells with IC50 values of 60 nM and 41 nM, respectively [51].
    Aurora-B small molecule inhibitors Various molecules reported as specific Aurora-B Kinase inhibitors are reported in following section (Structure of compounds 22 to 28 are shown in Fig. 3). Xie et al. reported compound 22 as Aurora-B inhibitor and found IC50 value of 0.735 μM. This compound was also screened over variety of human cancer cell lines with inhibition in range from 3.2 to 50 μM and HeLa cells was found the most sensitive to this compound. It was also evaluated in-vivo on xenograft model where it showed marked decreased in the TGI with 38.2% and 48.1% with 10 and 20 mg/kg dose, respectively [52].