S-3304 [(R)-3-(1H-indol-2-yl)-2-(5-(p-tolylethynyl)thiophene-2-sulfonamido)propanoic acid] a novel D-tryptophan derivative, is a potent, orally active, and noncytotoxic Matrix Metalloproteinases Inhibitor (MMPI). It is a noncytotoxic inhibitor of Matrix Metalloproteinases (MMPs), primarily MMP-2 and MMP-9, that prolongs survival in mice xenografts and is well tolerated in healthy volunteers.
It is being developed by Shionogi Pharmaceuticals.
MMP as Drug Target
The matrix metalloproteinases (MMP) are a large family of zinc-dependent endopeptidases, which play a fundamental role in cancer progression because of their ability to cleave virtually any component of the extracellular matrix (ECM) and basement membranes, thereby allowing cancer cells to penetrate and infiltrate the underlying stromal matrix and to access the vascular and lymphatic systems, which support tumor growth (angiogenesis) and constitute an escape route for further dissemination (invasion and metastasis). Elevated levels of MMPs can be detected in tumor tissue or serum of patients with advanced cancer, and their role as prognostic indicators in cancer has been widely examined. Among the MMPs, MMP-2 and MMP-9 degrade type IV collagen, which is a major component of the basement membranes, and their expression has been reported to correlate with tumor metastasis and angiogenesis in various cancers such as gastric, lung, bladder, nasopharyngeal, ovarian, breast, and head and neck [1].
Biochemical studies showed that S-3304 most potently inhibits the activities of MMP-2 and MMP-9 but does not inhibit MMP-1, MMP-3, or MMP-7 and may, therefore, lack the musculoskeletal side effects seen with nonspecific inhibitors. In vivo pharmacologic studies have shown that the oral administration of S-3304, at a dose range of 20 to 200 mg/kg, inhibited angiogenesis, artificially induced in mice by the dorsal air-sac method [2].
Phase I Trial
Phase I clinical trial were to determine the maximum tolerated dose, dose-limiting toxicities, pharmacokinetic profile, and intratumoral MMP inhibitory activity of single-agent S-3304 in advanced and refractory solid tumors. MMP activity was determined by film in situ zymography (FIZ). Patients had tumor biopsies before and after S-3304 administration and were also evaluated for response and survival [1].
Methodology
Four dose levels were explored [DL1-DL4 or 800, 1,600, 2,400, and 3200 mg twice daily (BID), respectively], and 32 patients were enrolled. Toxicities were mostly gastrointestinal. The maximum tolerated dose was not reached, but dose escalations beyond DL4 were impractical (number of capsules needed). S-3304 steady-state concentrations were reached by day 8, and day 1 mean C(max) and AUC(0-8) increases were less than dose proportional. After S-3304 administration, 17 of 18 patients experienced inhibition of MMP activity by FIZ. Strong mean inhibition of MMP activity was observed in DL1 to DL3.
Result
S-3304 is safe, well tolerated, and achieves plasma concentrations above those required to inhibit MMP-2 and MMP-9. Its intratumoral MMP inhibitory activity has been shown using FIZ, which is useful as a biomarker with this and other MMP inhibitors.
References:
1. Chiappori, A. A.; et. al. A phase I pharmacokinetic and pharmacodynamic study of s-3304, a novel matrix metalloproteinase inhibitor, in patients with advanced and refractory solid tumors. Clin Cancer Res 2007, 13(7), 2091-2099.
2. Yoshioka, T.; et. al. In vitro pharmacological profiles and in vivo anti-angiogenesis activity of S-3304, a novel matrix metalloproteinase inhibitor. Eur J Cancer 2002, 38, S81.
