From a MMP2/CK2 multitarget approach to the identification of potent and selective MMP13 inhibitors

Abstract

In this article, we describe new MMP13 inhibitors, active at low nanomolar concentrations, and with a novel TBB-derived scaffold.

Design and Synthesis of Water-Soluble and Potent MMP-13 Inhibitors with Activity in Human Osteosarcoma Cells

“…Thus, hydroxamates 1 and 2 presented activity in the low nanomolar range with IC 50 = 3.7 and 5.6 nM, respectively (Table 1). The activity of hydroxamate 1 against MMP-13 was the highest among all the tested MMPs (for selectivity of 1 see Table 2) [33]. 1 Calculated with Chemicalize-Instant Cheminformatics Solutions.…”

“…We expected this result because MMP-13 has a larger and slightly more flexible Ω-loop compared to that of other MMPs [ 38 ]. Therefore, the bulky tetrabromo benzotriazole group present in 1 and 2 is better stabilized by MMP-13 [ 33 ], while non-brominated compounds 9a and 9e bind to the active site of other isoforms with similar affinity. The results of the activity of 9a against a panel of MMPs are collected in Table 2 .…”

“…In previous work, we described polybrominated triazole derivatives 1 and 2 (Figure 2) with nanomolar inhibitory activity against MMP-13 (3.7 and 5.6 nM, respectively) and promising selectivity profiles against other MMPs [33]. In this work, we have extended A novel approach in the search for selective MMP-13 inhibitors is the use of docking techniques to carry out the screening of FDA-approved drugs against optimal human MMP-13 crystal structures.…”

“…In previous work, we described polybrominated triazole derivatives 1 and 2 ( Figure 2 ) with nanomolar inhibitory activity against MMP-13 (3.7 and 5.6 nM, respectively) and promising selectivity profiles against other MMPs [ 33 ]. In this work, we have extended the study to inhibitors based on phthalimide scaffolds and explored the influence of the bromine atoms with the aim of improving the potency/selectivity/solubility balance of this type of compound.…”

Molecular Imaging Probes Based on Matrix Metalloproteinase Inhibitors (MMPIs)

“…Our research group has designed, in the last years, highly potent and selective inhibitors of MMP-2, while avoiding other MMPs, including the highly homologous gelatinase MMP-9 [114,115,116,117,118]. The structure based drug design on MMP-13 carried out by the authors has also provided very interesting and highly selective inhibitors [119]. All these compounds constitute an important starting point for the development of imaging probes.…”