4r0i

Publication Abstract from PubMed

Matriptase is a cell-surface trypsin-like serine protease of epithelial origin, which cleaves and activates proteins including hepatocyte growth factor/scatter factor and proteases such as uPA, which are involved in the progression of various cancers. Here we report a fragment-linking approach, which led to the discovery of O-(3-carbamimidoylphenyl)-l-serine amides as potent matriptase inhibitors. The co-crystal structure of one of the potent inhibitors, 6 in complex with matriptase catalytic domain validated the working hypothesis guiding the development of this congeneric series and revealed the structural basis for matriptase inhibition. Replacement of a naphthyl group in 6 with 2,4,6-tri-isopropyl phenyl resulted in 10 with improved matriptase inhibition, which exhibited significant primary tumor growth inhibition in a mouse model of prostate cancer. Compounds such as 10, identified using a fragment-linking approach, can be explored further to understand the role of matriptase as a drug target in cancer and inflammation.

Discovery of O-(3-carbamimidoylphenyl)-l-serine amides as matriptase inhibitors using a fragment-linking approach.,Goswami R, Wohlfahrt G, Mukherjee S, Ghadiyaram C, Nagaraj J, Satyam LK, Subbarao K, Gopinath S, Krishnamurthy NR, Subramanya HS, Ramachandra M Bioorg Med Chem Lett. 2015 Feb 1;25(3):616-20. doi: 10.1016/j.bmcl.2014.12.008., Epub 2014 Dec 17. PMID:25556099^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.