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  • br Aurora A Aurora B and Aurora

    2024-07-09


    Aurora-A, Aurora-B and Aurora-C small molecule inhibitors Nicholas et al. described phenotypic cellular screening of new highly potent and selective class of Aurora kinase inhibitors. Fragment based approach was utilized; core structure of 57 (Fig. 5) was optimized and selective inhibitor 58 (Fig. 5) was synthesized which displayed many of the assurances of Aurora inhibition including endoreduplication, polyploidy, and loss of cancer cell viability. Compound 58 potently and selectively inhibited the enzymatic Aurora-A, Aurora-B and Aurora-C kinases with IC50 values of 5.6, 18.4, and 24.6 nM, respectively. When isoniazide were co-treated with Taxol in 100 nM concentration and compound 58, significant reduction observed in cell survival when compared to Taxol alone for 48 h time period. Compound 58 treatment produced premature exit from a Taxol-induced mitotic arrest constant with the belief that abrogation of mitotic arrest that diminished cell death caused by microtubule stabilizers. These experiments suggested that compound 58 inhibited the spindle assembly checkpoint very well [86], [87], [88].
    Clinical trial data Molecules reached at various stages of clinical trials are reported in following section and in Table 1 (Structure of compounds 59 to 69 are shown in Fig. 6).
    Preclinical candidates Following candidates are at advanced stages of preclinical studies (Structure of compounds 70 to 74 are shown in Fig. 7).
    Concluding remarks
    Future drug developement
    Conflict of interest
    Acknowledgment The Authors are thankful to Nirma University, Ahmedabad, India for providing necessary facilities to carry out the work, which is a part of Doctor of Philosophy (Ph.D) work of Ankit Borisa, to be submitted to Nirma University, Ahmedabad, India. The author AB is acknowledging Indian Council of Medical Research (ICMR), New Delhi, India for providing Senior Research Fellowship (File No:45/37/2015-PHA/BMS, IRIS-ID=2015-23870). The author HB is acknowledging Gujarat Council on Science and Technology (GUJCOST), Gandhinagar, India for sanctioning project (GUJCOST/MRP/2015-16/2670) to carry out the work.
    Introduction It is remarkable that much of spermatogenesis occurs in the absence of ongoing transcription and therefore must rely on post-translational modifications (PTMs) to regulate this process. Existing sperm proteins are subject to a wide range of PTMs to modulate their activity including phosphorylation, acetylation, glycylation, and sumoylation [1,2]. While well-defined signaling pathways such as MAPK and others are critical for spermatogenesis [3,4]; this complex developmental program likely involves a unique and varied array of phosphorylation/dephosphorylation pathways to regulate differentiation. Here we describe our discovery of a novel localization for a mitotic kinase, Aurora A (AURKA), in spermatids and spermatozoa. The family of Aurora kinases (AURKA, AURKB, and AURKC) are a related family of serine-threonine kinases with critical but distinct roles in cell division in somatic and germ cells [5]. AURKA has well-established roles in formation and function of the mitotic spindle. AURKA localizes to the centrosome and spindle fibers and is essential for centrosome maturation, separation, mitotic entry, and bipolar spindle assembly [6]. AURKB is a DNA passenger protein that functions in spindle checkpoint activation and is associated with kinetochores from prophase to anaphase and then is transported to the spindle midzone at telophase [7]. isoniazide AURKC is expressed primarily in the testis with proposed roles in meiosis [[8], [9], [10]].
    Methods and materials
    Results and discussion
    Conflicts of interest
    Acknowledgements The Authors acknowledge funding from the National Institutes of Health (HD030151) to A.O.S.
    Aurora Kinases Ipl1 was the first known member of the Aurora kinase family, discovered in yeast as a gene product involved in the control of ploidy (Ipl1 stands for ‘increase in ploidy #1′) [1]. Aurora kinase was then found in multicellular organisms, initially in Drosophila, where it was shown to control centrosome separation and bipolar spindle formation [2]. Three different Aurora kinases were then discovered in mammalian cells, and named Aurora A, B, and C [3].