The Inhibitor of Protein Kinase (IPK) Family

A wide variety of peptide macrocyclic compounds, forexample, indolocarbazoles, (Restituyo et al. 2015) are effective inhibitors of many protein kinases because they bind to the ATP binding sites of the kinases.  They include V-Src, Thr/Ser kinases, PKCs, cyclic AMP-dependent kinases, checkpoint kinases, etc (Yogarajah and Stone 2018).  These compounds include staurosporine, midostaurin, wortmannin, quercetin, myricetin, Ly294002 and many others (Stone et al. 2018).  They influence the ionic compositions of mitochondria and the cytoplasm and seem to dissipate the mitochondrial membrane potential (Arrebola et al. 2005).  They may do so by direct or indirect means.  Several of them have been used as anticancer drugs (Yogarajah and Stone 2018). Some of these drugs are made by Streptomyces species such as Streptomyces clavuligerus which makes staurosporine (Nakano and Omura 2009).


 

References:

Arrebola, F., S. Zabiti, F.J. Cañizares, M.A. Cubero, P.V. Crespo, and E. Fernández-Segura. (2005). Changes in intracellular sodium, chlorine, and potassium concentrations in staurosporine-induced apoptosis. J Cell Physiol 204: 500-507.

Nakano, H. and S. Omura. (2009). Chemical biology of natural indolocarbazole products: 30 years since the discovery of staurosporine. J Antibiot (Tokyo) 62: 17-26.

Restituyo, E., K. Camacho-Soto, and I. Ghosh. (2015). A fragment-based selection approach for the discovery of peptide macrocycles targeting protein kinases. Methods Mol Biol 1248: 95-104.

Stone, R.M., P.W. Manley, R.A. Larson, and R. Capdeville. (2018). Midostaurin: its odyssey from discovery to approval for treating acute myeloid leukemia and advanced systemic mastocytosis. Blood Adv 2: 444-453.

Yogarajah, M. and R.M. Stone. (2018). A concise review of BCL-2 inhibition in acute myeloid leukemia. Expert Rev Hematol 11: 145-154.