Screening of indeno[1,2-b]indoloquinones by MALDI-MS: a new set of potential CDC25 phosphatase inhibitors brought to light

Unexpected Binding Mode of a Potent Indeno[1,2-b]indole-Type Inhibitor of Protein Kinase CK2 Revealed by Complex Structures with the Catalytic Subunit CK2α and Its Paralog CK2α′

“…The indeno[1,2- b ]indole scaffold is a versatile and valuable lead structure to develop inhibitors targeting cancer associated proteins like protein kinase CK2 [ 50 , 51 ], the breast cancer resistance factor and ABC half transporter ABCG2 [ 52 ] and the phosphatase CDC25 [ 55 ]. Such efforts strongly benefit from experimental structure information about protein/inhibitor interactions which is presented here for the first time for an indeno[1,2- b ]indole-type CK2 inhibitor and which can be exploited for further optimization in the future.…”

“…This suggested interesting off-target effects with multi-drug resistance transport systems typically induced under cytotoxic conditions. This feature, further the flat and extended hydrophobic scaffold that resembled ATP-competitive CK2 inhibitors [ 41 ], and finally the plethora of functionalization opportunities provided by a tetracyclic ring system inspired ideas to use the indeno[1,2- b ]indole framework as the basis for polypharma-cology approaches: first Hundsdörfer et al [ 50 , 51 ] described a collection of indeno[1,2- b ]indole-type CK2 inhibitors all of them equipped with an oxo group at position 10 ( Figure 1 c–e) and the best of them with an attractive selectivity profile against a panel of 22 EPKs; later Gozzi et al [ 52 , 53 ] demonstrated how this indeno[1,2- b ]indole-10-one scaffold can be further derivatized at the rings A, C and D in different ways in order to create inhibitors targeting selectively either CK2 or the breast cancer resistance protein ABCG2—an ABC half transporter overexpressed in breast cancer cells [ 54 ]; and finally Alchab et al [ 55 ] extended this differentiation to a third cancer-relevant enzyme target, namely the cell cycle key phosphatase CDC25. In summary, with respect to the target CK2 about 50 indeno[1,2- b ]indole-based inhibitor candidates were described which have been recently clustered according to their D-ring substitution into a quinonic ( Figure 1 c), a phenolic ( Figure 1 d) and a ketonic ( Figure 1 e) subgroup [ 56 ].…”

A π-Halogen Bond of Dibenzofuranones with the Gatekeeper Phe113 in Human Protein Kinase CK2 Leads to Potent Tight Binding Inhibitors

“…Hence, an observed lack in selectivity must not be a flaw, but could even be beneficial if the compound addresses multiple targets related to the same disease and the interaction can be measured and as well be controlled by distinct structural features. First polypharmacology approaches of CK2 inhibitors with the aim to identify the structural requirements for inhibiting additional targets such as CDC25 and ABCG2 have been published recently [ 67 , 68 ]. Although we are still at beginning of the rational design of multi-target drugs, the understanding that addressing multiple targets could be beneficial for therapeutic intervention (and as such reflecting the multifactorial genesis of disease and re-echoing the observation of a poor correlation between in vitro drug effects and in vivo efficacy) will lead to completely new strategies in drug discovery.…”

An Unprecedented Synthesis of 8b-Hydroxy-3a-(1H-pyrrol-2-yl)/(1H-indol-3-yl)-3a,8b-dihydroindeno[1,2-b]pyrrol-4(1H)-one Derivatives from Pyrrole/Indole with Ninhydrin and β‑Enaminocarbonyls

“…14 Finally, indeno [1,2-b]pyrroles show many diverse biological activities. 15 Recent research on the synthesis of heterocycles incorporating pyrrole or pyrrolidine rings have attracted much attention, especially the syntheses of indenopyrrole derivatives have been of principal significance. 16 Indenopyrroles are prominent for their important biological activities as hypoglycemic agents 17 or as antagonists of N-methyl-D-aspartate receptor.…”