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  • Cardiogenesis is enhanced with timely applicati http www ape


    Cardiogenesis is enhanced with timely application of Wnt pathway activators and inhibitors. A combination of Wnt/β-catenin signaling pathway activators such as CHIR99021 and inhibitors such as IWP-2 and IWR-1 have been found to be highly efficient cardiomyocyte differentiation protocols [27], [28]. With the identification of 2,4,5-trisubstituted azoles as potent CK1δ/ε inhibitors, we have demonstrated an alternative method to inhibit the Wnt/β-catenin signaling pathway that could be used to induce cardiogenesis. Our cardiac differentiation protocol promotes cell growth during the differentiation process. CK1 inhibition does not lead to cell arrest or cytotoxicity [51], whereas other Wnt/β-catenin signaling pathway inhibitors such as IWP-2 and IWR-1 have been effectively used to inhibit cell growth [52], [53]. Although the growth inducing mechanism of TAs remains elusive our cardiac differentiation protocol is expected to yield 5z of higher quality. However, growth kinetics analyses with structurally different CK1 inhibitors during cardiac differentiation were not significantly improved (Supplemental Fig. 8). Hence it is likely that other off-targets that are unique to 2,4,5-trisubstituted azoles induced growth.
    Disclosure statement
    Acknowledgment and sources of funding We would like to thank Dr. Brain Lau, who helped us strongly with the editing and reviewing of the manuscript. The research was funded by the Joint Council Office (JCO), Agency for Science, Technology & Research (A*STAR), Singapore.
    Introduction As principal regulators of signal transduction pathways, protein kinases play a critical role in a wide range of cellular processes such as proliferation, differentiation and death (apoptosis). Protein kinases constitute the largest family of human enzymes and are considered to be the largest class amenable to therapeutic intervention by small molecule drugs [1], [2]. The clinical efficacy of kinase inhibitors such as Gleevec provides validation for the potential of drugs to modulate abnormal 5z kinase activities that have been implicated in a variety of cancers and other diseases [3], [4], [5]. With the advent of genome databases of clinically important protozoan parasites, it is clear that the evolutionary distance between essential protein kinases of the pathogen and orthologues of the host organism presents additional opportunities for chemotherapeutic intervention [6], [7]. That such differences can be successfully exploited has been confirmed in the case of the coccidian parasite cGMP-dependent protein kinase (PKG), for which selective inhibition by a small molecule inhibitor provides effective control of parasite proliferation [8], [9]. In this case, the compound (compound 1) prevents coccidiosis caused by Eimeria species in poultry and toxoplasmosis caused by Toxoplasma gondii in a mouse model [8], [10]. The existence of differences between parasite kinases and their host cell counterparts has also been suggested by affinity chromatography experiments, using an immobilized inhibitor of cyclin-dependent protein kinase (CDK) and protein micro-sequencing to identify bound proteins [11]. The ligand used in these studies, purvalanol B, is an exceptionally potent and selective inhibitor of mammalian CDKs that has been optimized through extensive medicinal chemistry including combinatorial approaches [12], [13], [14]. Affinity chromatography of parasite lysates with the purvalanol B matrix resulted unexpectedly in the identification of a tightly bound CK1 rather than CDK enzymes, from extracts of Plasmodium falciparum, Leishmania mexicana, T. gondii and Trypanosoma cruzi. In contrast, parallel affinity chromatography of extracts of marine invertebrates and some vertebrate tissues positively identified associated CDKs, but no CK1 enzymes were found. This intriguing differential affinity of parasite and host cell CDK and CK1 enzymes for the purvalanol B ligand suggests that both classes of enzyme harbor sufficient structural diversity to encourage exploration as potential antiparasitic targets.