Similarity searching for peptide-like small molecules is a difficult task because the amide backbone shared by these molecules tends to mask features that determine biological activity. We have investigated 2D fingerprints for their ability to differentiate between peptide-like molecules having different activity or to facilitate a peptidomimetic transition from molecules with strong peptide character to compounds having little or none. For these purposes, different compound activity classes were assembled consisting of molecules having strong, moderate, and weak peptide character. For the quantification of peptide character, a "peptide flavor" index was introduced. In systematic search calculations, an encouraging finding has been that most of the investigated 2D fingerprints were capable of distinguishing between peptide-like molecules having different activities. However, only two fingerprints of different design also displayed a strong tendency to detect molecules with decreasing peptide character. One of these search tools is a recently introduced property descriptor-based fingerprint that showed two additional advantages: its flexible design could be adjusted to increasingly recover molecules with little peptide-likeness, and in addition, its search performance was not affected by differences in molecular size.

01 Jul 1999·CarcinogenesisQ2 · MEDICINE

Expression of matrix metalloproteinase 2 (MMP-2), membrane-type 1 MMP and tissue inhibitor of metalloproteinase 2 and activation of proMMP-2 in pancreatic duct adenocarcinomas in hamsters treated with N-nitrosobis(2-oxopropyl)amine

Q2 · MEDICINE

Article

Author: Sakitani, Hiroyuki ; Takahama, Makoto ; Iki, Katsumichi ; Tatsumi, Kunihiko ; Konishi, Yoichi ; Kido, Akira ; Yoshimoto, Masatoshi ; Tsunoda, Tsukasa ; Motoyama, Masaaki ; Tsutsumi, Masahiro

In order to assess the significance of changes in metalloproteinase activity in pancreatic carcinogenesis, the expression of matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9, respectively), tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2, and membrane-type 1 MMP (MT1-MMP) and MT2-MMP in ductal lesions in a rapid-production model for pancreatic duct carcinomas (PCs) in hamsters initiated with N-nitrosobis(2-oxopropyl)amine (BOP) and in subcutaneous transplantable tumors of hamster pancreatic duct carcinoma (HPDs) was investigated. Northern analysis revealed MMP-2, MMP-9, TIMP-2 and MT1-MMP mRNAs to be overexpressed in PCs. Immunohistochemically, elevated levels of MMP-2 were apparent in early duct epithelial hyperplasias and staining increased from atypical hyperplasias to carcinomas. Gelatin zymography demonstrated clear activation of proMMP-2 but not proMMP-9 in both of primary and HPD tumors, the MT1-MMP mRNA level and proMMP-2 activation being significantly correlated (r = 0.893, P < 0.001). In our rapid production model, 0.1 and 0.2% OPB-3206, an inhibitor of MMPs, given in the diet after two cycles of augmentation pressures for 48 days decreased the incidence and number of carcinomas. Gelatin zymography demonstrated that OPB-3206 inhibited activation of proMMP-2 in pancreatic cancer tissues. These results indicate that overexpression of MMP-2, TIMP-2 and MT1-MMP, and cell surface activation of proMMP-2 by MT1-MMP, are involved in the development of PCs, and that MMP-2 expression at the protein level appears in the early phase of pancreatic duct carcinogenesis. OPB-3206 may be a candidate chemopreventive agent for pancreatic ductal adenocarcinomas.

01 Mar 1999·Japanese Journal of Cancer Research

Inhibition of Spontaneous Rat Osteosarcoma Lung Metastasis by 3S‐[4‐(Nhydroxyamino)‐2R‐isobutylsuccinyl]amino‐1‐methoxy‐3,4‐dihydrocarbostyril, a Novel Matrix Metalloproteinase Inhibitor

Article

Author: Akira Kido ; Masahiro Tsutsumi ; Yoichi Konishi ; Masaaki Motoyama ; Katsumichi Iki ; Makoto Takahama ; Kunihiko Tatsumi ; Toru Morishita ; Toshifumi Tsujiuchi ; Susumu Tamai

In the present experiment, we examined the effects of OPB‐3206, 3S‐[4‐(N‐hydroxyamino)‐2R isobutylsuccinyl] amino‐1‐methoxy‐3,4‐dihydrocarbostyril, a novel metalloproteinase inhibitor, on the growth and metastasis of transplantable osteosarcomas (spontaneous osteosarcoma, selected lung metastatic lesions; S‐SLM), which were previously established in rats. OPB‐3206 inhibited the activities of interstitial collagenase, gelatinases A and B, and stromelysin in vitro. After oral administration to rats, its serum concentration peaked at 40 min and the drug was no longer detectable at 8 h. When OPB‐3206 was orally administered at 0%, 0.1% and 0.4% in the diet for 4 weeks, starting 7 days after subcutaneous transplantation of osteosarcomas to male Fischer 344 rats, numbers of lung metastatic nodules were significantly reduced by the highest dose, while the growth of subcutaneous tumors was not affected. Zymographic analysis showed the presence of pro matrix metalloproteinase (proMMP)‐2, proMMP‐9 and MMP‐9 activities in S‐SLM. In animals fed 0.4% OPB‐3206, the activity of proMMP‐9 was increased, but that for MMP‐9 had become undetectable. The results thus suggest that OPB‐3206 selectively inhibits lung metastasis of rat transplantable osteosarcomas by inhibiting MMP‐9 activation.

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Indication	Highest Phase	Country/Location	Organization	Date
Neovascularization, Pathologic	Preclinical	Japan	Otsuka Pharmaceutical Co., Ltd.	17 Dec 1997
Neoplasms	Preclinical	Japan	-	-
Neoplasms	Preclinical	Japan	-	-

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