ARP 100

ARP 100 is a selective inhibitor of matrix metalloproteinases 2 (MMP-2) with IC50 value of 12 nM [1].
Proteins of the matrix metalloproteinase (MMP) family are involved in the breakdown of extracellular matrix in normal physiological processes, such as embryonic development, reproduction, and tissue remodeling, as well as in disease processes, such as arthritis and metastasis (http://en.wikipedia.org/wiki/MMP2). ARP 100 is a selective inhibitor of matrix metalloproteinases 2 (MMP-2).
In vitro: As a potent derivative of N-arylsulfonyl-N-alkoxyaminoacetohydroxamic acids, ARP 100, shows similar anti-invasive properties to the analogue reference drug CGS27023A, in an in vitro model of invasion on matrigel, carried out on cellular lines of fibrosarcoma HT1080 (tumoural cells over-expressing MMP-2 and MMP-9) [1].
In silico: ARP 100 proved to be practically inactive in the MMP-1; this was probably due to the presence of the biphenyl group, since this substituent was not able to interact in the S10 pocket, and this fact determined the loss of the interaction of the oxygen atoms of the sulfonamido group with Ala182 and Leu181. ARP 100 was also found to be the most selective ligand of the four analyzed, and this fact could be due to the presence of a large P10 group, rigid and unable to form H bonds, or to interact with the MMP-1-S10 pocket. This analysis suggested that in order to maintain the MMP-2/MMP-1 selectivity, the presence of the biphenyl group as a P10 substituent could be very useful [2].
Clinical trial: ARP 100 is currently in the preclinical development and no clinical trial is ongoing.
References:
[1] Rossello A, Nuti E, Orlandini E, Carelli P, Rapposelli S, Macchia M, Minutolo F, Carbonaro L, Albini A, Benelli R, Cercignani G, Murphy G, Balsamo A. New N-arylsulfonyl-N- alkoxyaminoacetohydroxamic acids as selective inhibitors of gelatinase A (MMP-2). Bioorg Med Chem. 2004;12(9):2441-50.
[2] Tuccinardi T, Martinelli A, Nuti E, Carelli P, Balzano F, Uccello-Barretta G, Murphy G, Rossello A.Amber force field implementation, molecular modelling study, synthesis and MMP-1/MMP-2 inhibition profile of (R)- and (S)-N-hydroxy-2-(N-isopropoxybiphenyl-4-ylsulfonamido)- 3-methylbutanamides. Bioorg Med Chem. 2006;14(12):4260-76.

Inhibitory effects of caspase inhibitors on the activity of matrix metalloproteinase-2.[Pubmed:23774623]

Biochem Pharmacol. 2013 Aug 15;86(4):469-75.

Matrix metalloproteinase (MMP)-2, a zinc-dependent endopeptidase, plays a detrimental role in several diseases including ischemia and reperfusion (I/R) injury of the heart. Caspases are a group of cysteine-dependent, aspartate-directed proteases which regulate cellular apoptosis. Interestingly, protective effects of caspase inhibitors independent of apoptosis have been shown in I/R injury of the heart. The cardioprotective actions of both these classes of protease inhibitors led us to hypothesize that caspase inhibitors may also reduce MMP-2 activity. Five known caspase inhibitors (Z-IE(OMe)TD(OMe)-fmk, Ac-DEVD-CHO, Ac-LEHD-cmk, Z-VAD-fmk and Ac-YVAD-cmk) were tested for their possible inhibitory effects on MMP-2 activity in comparison to the MMP inhibitors ONO-4817 and ARP-100 (which themselves were unable to inhibit caspase-3 activity). MMP-2 activity was assessed by an in vitro troponin I (TnI) proteolysis assay and a quantitative kinetic fluorescence assay using a fluorogenic peptide substrate (OmniMMP). TnI proteolysis was also measured by western blot in neonatal cardiomyocytes subjected to hypoxia-reoxygenation injury. Using human recombinant MMP-2 and TnI as its substrate, the caspase inhibitors, in comparison with ONO-4817, significantly inhibited MMP-2-mediated TnI degradation in a concentration-dependent manner. The kinetic assay using OmniMMP revealed that these caspase inhibitors blocked MMP-2 activity in a concentration-dependent manner with similar IC50 values. TnI degradation in neonatal cardiomyocytes was enhanced following hypoxia-reoxygenation and this was blocked by ARP-100 and Ac-LEHD-cmk. Inhibition of MMP-2 activity is an additional pharmacological action which contributes to the protective effects of some caspase inhibitors.

Matrix metalloproteinase-2 in oncostatin M-induced sarcomere degeneration in cardiomyocytes.[Pubmed:27199120]

Am J Physiol Heart Circ Physiol. 2016 Jul 1;311(1):H183-9.

Cardiomyocyte dedifferentiation may be an important source of proliferating cardiomyocytes facilitating cardiac repair. Cardiomyocyte dedifferentiation and proliferation induced by oncostatin-M (OSM) is characterized by sarcomere degeneration. However, the mechanism underlying sarcomere degeneration remains unclear. We hypothesized that this process may involve matrix metalloproteinase-2 (MMP-2), a key protease localized at the sarcomere in cardiomyocytes. We tested the hypothesis that MMP-2 is involved in the sarcomere degeneration that characterizes cardiomyocyte dedifferentiation. Confocal immunofluorescence and biochemical methods were used to explore the role of MMP-2 in OSM-induced dedifferentiation of neonatal rat ventricular myocytes (NRVM). OSM caused a concentration- and time-dependent loss of sarcomeric alpha-actinin and troponin-I in NRVM. Upon OSM-treatment, the mature sarcomere transformed to a phenotype resembling a less-developed sarcomere, i.e., loss of sarcomeric proteins and Z-disk transformed into disconnected Z bodies, characteristic of immature myofibrils. OSM dose dependently increased MMP-2 activity. Both the pan-MMP inhibitor GM6001 and the selective MMP-2 inhibitor ARP 100 prevented sarcomere degeneration induced by OSM treatment. OSM also induced NRVM cell cycling and increased methyl-thiazolyl-tetrazolium (MTT) staining, preventable by MMP inhibition. These results suggest that MMP-2 mediates sarcomere degeneration in OSM-induced cardiomyocyte dedifferentiation and thus potentially contributes to cardiomyocyte regeneration.

MMP-2 alters VEGF expression via alphaVbeta3 integrin-mediated PI3K/AKT signaling in A549 lung cancer cells.[Pubmed:20027628]

Int J Cancer. 2010 Sep 1;127(5):1081-95.

Vascular endothelial growth factor (VEGF) is one of the most important angiogenic growth factors for tumor angiogenesis. Here, we sought to explore whether RNA interference (RNAi) targeting matrix metalloproteinase-2 (MMP-2) could disrupt VEGF-mediated angiogenesis in lung cancer. MMP-2 siRNA inhibited lung cancer cell-induced tube formation of endothelial cells in vitro; addition of recombinant human-MMP-2 restored angiogenesis. MMP-2 transcriptional suppression decreased VEGF, phosphatidylinositol 3-kinase (PI3K) protein levels and AKT phosphorylation in lung cancer cells. In addition, MMP-2 suppression decreased hypoxia inducible factor-1alpha (HIF-1alpha), a transcription factor for VEGF, as determined by electrophoretic mobility shift assay (EMSA). We also show that MMP-2 suppression disrupted PI3K dependent VEGF expression; ectopic expression of myr-AKT restored VEGF inhibition. Further, MMP-2 suppression decreased the interaction of integrin-alphaVbeta3 and MMP-2 as confirmed by immunoprecipitation analyses. Studies with either function blocking integrin-alphaVbeta3 antibody or MMP-2 specific inhibitor (ARP-100) indicate that suppression of MMP-2 decreased integrin-alphaVbeta3-mediated induction of PI3K/AKT leading to decreased VEGF expression. Moreover, A549 xenograft tissue sections from mice that treated with MMP-2 siRNA showed reduced expression of VEGF and the angiogenic marker, factor-VIII. The inhibition of tumor angiogenesis in MMP-2 suppressed tumor sections was associated with decreased co-localization of integrin-alphaVbeta3 and MMP-2. In summary, these data provide new insights into the mechanisms underlying MMP-2-mediated VEGF expression in lung tumor angiogenesis.

Amber force field implementation, molecular modelling study, synthesis and MMP-1/MMP-2 inhibition profile of (R)- and (S)-N-hydroxy-2-(N-isopropoxybiphenyl-4-ylsulfonamido)-3-methylbutanamides.[Pubmed:16483784]

Bioorg Med Chem. 2006 Jun 15;14(12):4260-76.

Ab initio calculations (B3LYP/Lanl2DZ level of theory) were performed in this study to determine all the structural and catalytic zinc parameters required in order to study MMPs and their complexes with hydroxamate inhibitors by means of the AMBER force field. The parameters thus obtained were used in order to study the docking of some known MMPi (Batimastat, CGS 27023A and Prinomastat) and our previously described inhibitor a which had shown an inhibitory activity for MMP-1, and -2, with the aim of explaining the different selectivity. On this basis the two enantiomers (R)-b and (S)-b were designed and synthesized, as more potent MMP-2 inhibitors than our previously described inhibitor a. Between these two enantiomers the eutomer (R)-b proved to be 24.7 times and 15.3 times more potent than CGS 27023A and the parent compound a on MMP-2, maintaining a higher index of MMP-2/MMP-1 selectivity compared with CGS 27023A and the more potent inhibitor Prinomastat. The hydroxamate (R)-b can be considered as a progenitor of a new class of biphenylsulfonamido-based inhibitors that differ from compound a in the presence of an alkyl side chain on the C alpha atom, and show different potency and selectivity profiles on the two MMPs considered.

New N-arylsulfonyl-N-alkoxyaminoacetohydroxamic acids as selective inhibitors of gelatinase A (MMP-2).[Pubmed:15080939]

Bioorg Med Chem. 2004 May 1;12(9):2441-50.

New N-arylsulfonyl-substituted alkoxyaminoaceto hydroxamic acid derivatives of types 8 and 10 designed as oxa-analogues of known sulfonamide-based MMPi of types 2 and 7 were synthesized and tested for their inhibitory activities on some matrix metalloproteinases. The combination of a biphenylsulfonamide group with oxyamino oxygen in the pharmacophoric central skeleton of sulfonamide-based MMPi obtained in the new sulfonamides 10 seems to be able to give selectivity for MMP-2 over MMP-1. The most potent derivative of this type, 10a, shows similar anti-invasive properties to the analogue reference drug CGS27023A, 2, in an in vitro model of invasion on matrigel, carried out on cellular lines of fibrosarcoma HT1080 (tumoural cells over-expressing MMP-2 and MMP-9).

ARP-100 is a potent and selective matrix metalloproteinase MMP-2 inhibitor (IC50=12 nM). ARP-100 interacts with S1＇ pocket of MMP-2 and shows anti-invasive properties in an in vitro model of invasion on matrigel. ARP-100 shows the less inhibitory activity towards MMP-1 (>50 μM), MMP-3 (4.5 μM), MMP-7 (>50 μM), and MMP-9 (0.2 μM).

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