Structure–Activity Relationship Studies on Isoindoline Inhibitors of Dipeptidyl Peptidases 8 and 9 (DPP8, DPP9): Is DPP8-Selectivity an Attainable Goal?

Abstract

This work represents the first directed study to identify modification points in the topology of a representative DPP8/9-inhibitor, capable of rendering selectivity for DPP8 over DPP9. The availability of a DPP8-selective compound would be highly instrumental for studying and untwining the biological roles of DPP8 and DPP9 and for the disambiguation of biological effects of nonselective DPP-inhibitors that have mainly been ascribed to blocking of DPPIV's action. The cell-permeable DPP8/9-inhibitor 7 was selected as a lead and dissected into several substructures that were modified separately for evaluating their potential to contribute to selectivity. The obtained results, together with earlier work from our group, clearly narrow down the most probable DPP8-selectivity imparting modification points in DPP8/9 inhibitors to parts of space that are topologically equivalent to the piperazine ring system in 7. This information can be considered of high value for future design of compounds with maximal DPP8 selectivity.

Selective Inhibitors of Fibroblast Activation Protein (FAP) with a (4-Quinolinoyl)-glycyl-2-cyanopyrrolidine Scaffold

“…19 It is worthwhile to stipulate that DPP9 potencies reported can reasonably be expected to also be indicative for inhibitor affinities toward the highly homologous DPP8. 26,27 The results summarized in Table 2 show that the N-(4-quinolinoyl) substituted compound 7 has about 60 times more FAP-affinity than the initial N-(1-naphthoyl) based 'hit' 3. Its potency as an inhibitor of FAP also clearly stands out among the other compounds in Table 2.…”

A Novel SUMO1-specific Interacting Motif in Dipeptidyl Peptidase 9 (DPP9) That Is Important for Enzymatic Regulation

“…A similar model was published by (41). Homology models were successfully used for analyzing and designing inhibitors with increased specificity for DPP8 and DPP9 over DPPIV (42). Crystal structures of members of the DPPIV family show that they all form homodimers, where each monomer is build of two domains, a barrel-like ␣/␤ hydrolase and an eight-blade ␤ propeller.…”

The SUMO1-E67 Interacting Loop Peptide Is an Allosteric Inhibitor of the Dipeptidyl Peptidases 8 and 9

“…All inhibitors described so far are competitive and target both DPP8 and DPP9 (32)(33)(34)(35)(36). The best selectivity was described recently by Van Goethem et al (36), who systematically dissected and modified the DPP8/9 inhibitor 1G244 to increase the selectivity of the inhibitor toward DPP8.…”

“…The best selectivity was described recently by Van Goethem et al (36), who systematically dissected and modified the DPP8/9 inhibitor 1G244 to increase the selectivity of the inhibitor toward DPP8. This analysis led to identification of compound 12n, which showed a 10-fold selectivity toward DPP8 when measuring IC 50 values and a 6.4 selectivity for DPP8 over DPP9 in K i values (36).…”

“…The best selectivity was described recently by Van Goethem et al (36), who systematically dissected and modified the DPP8/9 inhibitor 1G244 to increase the selectivity of the inhibitor toward DPP8. This analysis led to identification of compound 12n, which showed a 10-fold selectivity toward DPP8 when measuring IC 50 values and a 6.4 selectivity for DPP8 over DPP9 in K i values (36). Allosteric inhibitors are emerging as a promising alternative approach to competitive inhibitors, which are more prone to off-target side effects caused by the high conservation of the catalytic sites (37)(38)(39).…”