Inhibitors of protein kinase C. 2. Substituted bisindolylmaleimides with improved potency and selectivity

Abstract

A hypothetical mode of inhibition of protein kinase C (PKC) by the natural product staurosporine has been used as a basis for the design of substituted bisindolylmaleimides with improved potency over the parent compound. Structure-activity relationships were consistent with the interaction of a cationic group in the inhibitor with a carboxylate group in the enzyme, and the most potent compound had a Ki of 3 nM. The inhibitors were competitive with ATP but inhibited cAMP-dependent protein kinase (PKA) only at much higher concentrations despite the extensive sequence homology between the ATP-binding regions of PKA and PKC. Three compounds were evaluated further and found to inhibit a human allogeneic mixed lymphocyte reaction pointing to the potential utility of PKC inhibitors in immunosuppressive therapy. One of these compounds was orally absorbed in the rat and represents an attractive lead in the development of PKC inhibitors as drugs.

Differential inhibition of cytosolic and membrane‐derived protein kinase C activity by staurosporine and other kinase inhibitors

“…Six of the agents studied here, H-7 [20], staurosporine [6] and its cogeners UCN-01 [7], RO 31 8220 [8], CGP 41251 [9] and GF 109203X [10], are thought to inhibit PKC at the catalytic site. Three of them, calphostin C [21], NPC 15-437 [22] and miltefosine [23] act at the regulatory domain of the enzyme.…”

“…Staurosporine and RO 31 8220 exhibited IC50 ratios of 12.3 and 21.6, respectively. The results suggest that there are dramatic differences between kinase inhibitors in their divergent effects on cytosolic and membrane-derived PKC which should be borne in mind in the interpretation of their pharmacological properties.but possess much better selectivity for PKC [7][8][9][10]. Two such PKC-specific analogues, UCN-01 and CGP 41251, have been shown to possess antineoplastic activity in human tumour models grown in rodents [9,11].…”

“…but possess much better selectivity for PKC [7][8][9][10]. Two such PKC-specific analogues, UCN-01 and CGP 41251, have been shown to possess antineoplastic activity in human tumour models grown in rodents [9,11].…”

Reactivation of Fetal Splicing Programs in Diabetic Hearts Is Mediated by Protein Kinase C Signaling

“…Hearts-To test whether PKC␣/␤ regulates fetal to adult-specific AS transitions, we used BisIX, a small molecule inhibitor that preferentially blocks the activity of PKC␣/␤ at low doses (34). H9c2 cells were either mocktreated or treated with BisIX and differentiated for 7 days.…”

Drug discovery approaches targeting the PI3K/Akt pathway in cancer

“…Akt isoforms are potently inhibited by promiscuous kinase inhibitors like staurosporine (compound 20, Figure 4; IC 50 ¼ 48-11 nM for Akt1) and derivatives thereof (for example, compound 21, Figure 4) (Kumar et al, 2001;Li and Zhu, 2002). Similarly, Ro-31-8220 (compound 22, Figure 4) is a potent, but nonselective pan-Akt inhibitor, with primary activity against PKC (IC 50 ¼ 10 nM) (Davis et al, 1992) and more modest activity against Akt1 (IC 50 ¼ 240 nM).…”