8.08 – Tepotinib

TLDR: This article is dedicated to the identification and in-depth characterization of tepotinib, an exquisitely selective c-Met inhibitor that is currently evaluated in clinical trials.

Abstract: The activation of c-Met (mesenchymal–epithelial transition factor receptor), also known as hepatocyte growth factor receptor (HGFR), is associated with a variety of oncological malignancies including cancers of the lung, kidney, stomach, liver, and brain. Our efforts to develop an inhibitor for this highly validated target started with the identification of 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) as an already highly selective and reasonably potent hit in our high-throughput screening campaign. Guided by c-Met cocrystal structures and rational drug design, suitable thiadiazinone core replacements like pyridazinones or benzoxazolones were identified. This optimization followed by a subsequent exchange of the generic carbamate hinge-binding element with a more versatile 1,5-disubstituted pyrimidine finally led to the identification of a potent and selective inhibitor of the proto-oncogene c-Met. This article is dedicated to the identification and in-depth characterization of tepotinib, an exquisitely selective c-Met inhibitor that is currently evaluated in clinical trials.