The membrane-type 1 matrix metalloproteinase (MT1-MMP) has been reported to mediate the activation of pro-gelatinase A (proMMP-2), which is associated with tumor proliferation and metastasis. MT1-MMP can also digest extracellular matrix (ECM) such as interstitial collagens, gelatin, and proteoglycan and thus may play an important role in pathophysiological digestion of ECM. We studied the inhibitory effect of various hydroxamate MMP inhibitors, including known inhibitors such as BB-94, BB-2516, GM6001, and Ro31-9790, on a deletion mutant of MT1-MMP lacking the transmembrane domain (DeltaMT1) to further characterize the enzyme and develop a selective inhibitor for MT1-MMP. The evaluation of the inhibitory activities of various hydroxamates reveals general structural profiles affecting selectivities toward MMPs. In particular, a longer side chain at the P1' position is preferable for the binding to MMP-2, -3, and -9 and MT1-MMP. For the P2' position, an alpha-branched alkyl group is critical for the binding toward DeltaMT1, while the introduction of a bulky group at the alpha-position of hydroxamic acid seems to diminish the activity against DeltaMT1. Summation of the data on the sensitivity of DeltaMT1 to various hydroxamate inhibitors indicates that (1) the volume of the S1' subsite of DeltaMT1 is similar to that of MMP-2, -3, and -9, which is bigger than that of MMP-1, and (2) the S1 and S2' subsites are narrower than those in other MMPs. On the basis of these results, the hydroxamates with a P1' phenylpropyl and P2' alpha-branched alkyl group were synthesized and evaluated for inhibitory activity. These inhibitors (1h,i) showed strong activity against DeltaMT1 over MMP-1, but no selectivity between DeltaMT1 and MMP-9. These results are explained using molecular modeling studies conducted on MT1-MMP.

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S U M M A R YThe Miocene basaltic-andesitic lavas and Cretaceous granites were sampled in the Abukuma Terrane of northeast Honshu for geochronological and palaeomagnetic investigations to determine precise timing of counter-clockwise rotation of NE Japan. Characteristic component with unblocking temperature of 560-590 • C is isolated from 26 sites of the Takadate and Ryozen Formations and 12 sites of the Cretaceous granites. Concordant northwesterly palaeomagnetic directions (D = 265 • -331 • ) are observed in the Cretaceous granites of the Abukuma Terrane. The Cretaceous mean-palaeomagnetic direction from this terrane (D = 313.5 • , I = 54.6 • , α 95 = 6.3 • and N = 20) is almost identical to Oligo-Miocene (33-20 Ma) palaeomagnetic direction reported from the Japan Sea side of NE Japan as well as to the Cretaceous palaeomagnetic direction reported from the Kitakami Terrane. This type of behaviour clearly suggests that the Abukuma Terrane underwent a coherent counter-clockwise rotation as a part of NE Japan after 20 Ma. Conventional potassium (K)-Argon (Ar) dating method performed on the plagioclase grains revealed distinctive ages of 14.44 ± 0.88 and 16.52 ± 0.82 Ma for the Takadate Formation (11 sites) and the Ryozen Formation (eight sites), respectively. This type of behaviour indicates that two independent episodes of volcanic activities were probably responsible for the production of igneous rocks in the Takadate and Ryozen areas. Northerly declination is obtained from the Takadate Formation (D = 355.3 • , I = 39.4 • , α 95 = 11.6 • ), while slightly westerly deflected declination appears in the Ryozen Formation (D = 333.5 • , I = 58.0 • and α 95 = 9.6 • ). The here presented results, therefore, suggest that the province of NE Japan was still experiencing a counter-clockwise rotation at 16.5 Ma, however by 14.4 Ma the rotational motion has completely ceased. Compared with the available palaeomagnetic and geochronological data from SW Japan, rotational motion in both provinces of NE and SE Japan has already been ceased by 14 Ma. Thus any additional evidence regarding the complete cessation of rotational motions in NE Japan will provide a key to understand the timing of opening in the Japan Sea.

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