Beschreibung:
<jats:title>Abstract</jats:title>
<jats:p>The role of the receptor tyrosin kinase c-Met in tumor progression and metastasis has been shown in preclinical studies and in early clinical settings. Several c-Met inhibitors with different selectivity profiles are currently in preclinical/clinical investigation and might provide effective cancer therapeutics in the future.</jats:p>
<jats:p>A biochemical HTS run using the recombinant kinase domain of c-Met enabled us to identify N-(3-(3,6-Dihydro-5-(3,4-dimethoxyphenyl)-2-oxo-2H-1,3,4-thiadiazin-3-ylmethyl)-phenyl)-carbaminic acid-(3-(N,N-diethylamino)-propylester) representing as new chemical class of kinase inhibitors. This HTS hit inhibited c-Met in vitro kinase activity and HGF-induced c-Met phosphorylation in A459 lung cancer cells with IC50 values well below 1 µM. The analysis of co-crystal structures defined the molecular requirements for potency and selectivity and guided the subsequent chemical optimization. As a result of the lead optimization process, two candidate compounds with distinct pharmacological properties were synthesized, EMD 1214063 and EMD 1204831. Both compounds are highly potent and efficient inhibitors of c-Met in vitro kinase activity and c-Met auto-phosphorylation induced in vitro by HGF stimulation or by c-Met overexpression. Both compounds displayed an exquisite selectivity profile when tested in vitro against a panel of more than 250 potential off-targets, including kinases, GPCRs, ion channels, transporters and various enzymes.</jats:p>
<jats:p>EMD 1214063 and EMD 1204831 exhibited excellent anti-tumor activity in vivo in a variety of xenograft models, including U87-MG glioblastoma cells (autocrine HGF production), TPR-Met-transformed mouse fibroblasts (oncogenic Met fusion protein) or Hs746T gastric and EBC-1 lung cancer cells (c-Met gene amplification and HGF-independent activation).</jats:p>
<jats:p>In c-Met-driven models complete regressions were observed with doses as low as 6 mg/kg/d administered per os. PK/PD analysis revealed efficient, dose- and time-dependent inhibition of c-Met phosphorylation, reduction of IL-8 and cyclin D1 expression as well as an induction of the cell cycle inhibitor p27. The pharmacodynamic effects of EMD 1214063 were longlasting and allowed various schedule variations without compromising its anti-tumor activity, while c-Met inhibition by EMD 1204831 was rather transient, allowing optimal anti-tumor activity when the compound was applied once or twice daily.</jats:p>
<jats:p>The profile of EMD 1214063 and EMD 1204831 including synthesis, structure activity relationships, X-ray structures and a comprehensive pharmacological in vitro and in vivo characterization will be presented. Furthermore, potential pharmacodynamic and predictive biomarkers will be discussed.</jats:p>
<jats:p>Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B252.</jats:p>