4O97

Crystal structure of matriptase in complex with inhibitor

Summary for 4O97

• Entry DOI: 10.2210/pdb4o97/pdb
• Related: 4O9V
• Descriptor: Suppressor of tumorigenicity 14 protein, Peptide CGLR, N-(trans-4-aminocyclohexyl)-3,5-bis[(3-carbamimidoylbenzyl)oxy]benzamide, ... (4 entities in total)
• Functional Keywords: matriptase, trypsin-like serine proteinase fold, protease, small molecule inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human); More
• Cellular location: Membrane; Single-pass type II membrane protein (Probable): Q9Y5Y6 Q9Y5Y6
• Total number of polymer chains: 2
• Total formula weight: 27426.94

Authors

Rao, K.N.,Chandra, B.R.,Ashok, K.N.,Chakshusmathi, G.,Ramesh, K.S.,Subramanya, H.S. (deposition date: 2014-01-02, release date: 2014-05-28, Last modification date: 2024-10-30)

Primary citation

Goswami, R.,Mukherjee, S.,Ghadiyaram, C.,Wohlfahrt, G.,Sistla, R.K.,Nagaraj, J.,Satyam, L.K.,Subbarao, K.,Palakurthy, R.K.,Gopinath, S.,Krishnamurthy, N.R.,Ikonen, T.,Moilanen, A.,Subramanya, H.S.,Kallio, P.,Ramachandra, M.
Structure-guided discovery of 1,3,5 tri-substituted benzenes as potent and selective matriptase inhibitors exhibiting in vivo antitumor efficacy.
Bioorg.Med.Chem., 22:3187-3203, 2014

PubMed Abstract: Matriptase is a serine protease implicated in cancer invasion and metastasis. Expression of matriptase is frequently dysregulated in human cancers and matriptase has been reported to activate latent growth factors such as hepatocyte growth factor/scatter factor, and proteases such as urokinase plasminogen activator suggesting that matriptase inhibitors could have therapeutic potential in treatment of cancer. Here we report a structure-based approach which led to the discovery of selective and potent matriptase inhibitors with benzene as central core having 1,3,5 tri-substitution pattern. X-ray crystallography of one of the potent analogs in complex with matriptase revealed strong hydrogen bonding and salt-bridge interactions in the S1 pocket, as well as strong CH-π contacts between the P2/P4 cyclohexyl and Trp215 side-chain. An additional interaction of the pendant amine at cyclohexyl with Gln175 side-chain results in substantial improvement in matriptase inhibition and selectivity against other related serine proteases. Compounds 15 and 26 showed tumor growth inhibition in a subcutaneous DU-145 prostate cancer mouse model. These compounds could be useful as tools to further explore the biology of matriptase as a drug target.

PubMed: 24794746
DOI: 10.1016/j.bmc.2014.04.013

Experimental method

X-RAY DIFFRACTION (2.2 Å)