Kinase allosteric modulators

Flavone has been shown to be effective at 170 /iM concentration to inhibit HDAC-1 activity, and also to induce histone H3 acetylation in NB4 APL cell lines. Flavone s mechanism of HDAC inhibition is currently unknown, but it has been proposed that similar to the inhibitors of kinases, it might occupy the exit channel or an alternative, shallow binding site found in HDAC with possible effects of causing allosteric modulation. This blockage or allosteric modulation would promote inhibition. ... 

Lewis, J.A., Lebois, E.P., and Lindsley, C.W. (2008) Allosteric modulation of kinases and GPCRs Design principles and structural diversity. Curr. Opin. Chem. Biol. 12, 269-80. 

Herlitze, S., Zhong, H., Scheur, T. and Catterall, W.A. (2001) Allosteric modulation of Ca channels by G-proteins, voltage-dependent facilitation, protein kinase C, and Ca(v)beta subunits. Proc. Natl Acad. Sci. USA 98 4699-4704. 

Fang, Z., Grutter, C., and Rauh, D. (2013) Strategies for the selective regulation of kinases with allosteric modulators exploiting exclusive structural features. ACS Chem. Biol., 8 (1), 58-70. 

Due to the large number of available protein structures, kinases still have to be considered the best case for structure-based library design. This is even truer for targeting allosteric modulation [124]. Here, a group of inhibitors has been inden-tified that bind outside the ATP pocket and, thereby, stabilize the DFG motif. 

The fact that the aliosterically preferred conformation may be relatively rare in the library of conformations available to the receptor may have kinetic implications. Specifically, if the binding site for the modulator appears only when the preferred conformation is formed spontaneously, then complete conversion to alios terically modified receptor may require a relatively long period of equilibration. For example, the allosteric p38 MAP kinase inhibitor BIRB 796 binds to a conformation of MAP kinase requiring movement of a Phe residue by 10 angstroms (so-called out conformation). The association rate for this modulator is 8.5 x 105 M-1 s-1, 50 times slower than that required for other inhibitors (4.3 x 107 M 1 s-1). The result is that while other inhibitors reach equilibrium within 30 minutes, BIRB 376 requires 2 full hours of equilibration time [8],... 

The central function of Ptdlns(3,4,5)P3 is to bind to pleckstrin homology domains (PH domains) of signal proteins. PH domains are found as independent protein modules in many signal proteins (see Chapter 8.2.4) that mediate protein-lipid and possibly also protein-protein interactions. Ptdlns(3,4,5)P3 formed by P13-kinase serves to recruit signal molecules next in sequence to the membrane and to involve them in signal conduction. In addition, Ptdlns(3,4,5)P3 can also bring about an allosteric activation of its effector proteins. 

Inhibitors of the active form of the kinase are classified as Type I inhibitors, and inhibitors of inactive forms of the kinases are Type II inhibitors. Recently, there has been considerable interest in identifying additional binding sites remote from the active site but which can modulate kinase activity. Inhibitors binding to such allosteric or substrate sites would be considered type III inhibitors. 

Figure 10.3 Representative examples of allosteric kinase modulators.

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