4o97 | pdb_00004o97
Crystal structure of matriptase in complex with inhibitor
Structural highlights
Disease[ST14_HUMAN] Defects in ST14 are a cause of ichthyosis autosomal recessive with hypotrichosis (ARIH) [MIM:610765]. ARIH is a skin disorder characterized by congenital ichthyosis associated with the presence of less than the normal amount of hair.[1] Function[ST14_HUMAN] Degrades extracellular matrix. Proposed to play a role in breast cancer invasion and metastasis. Exhibits trypsin-like activity as defined by cleavage of synthetic substrates with Arg or Lys as the P1 site. Publication Abstract from PubMedMatriptase 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-pi 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. Structure-guided discovery of 1,3,5 tri-substituted benzenes as potent and selective matriptase inhibitors exhibiting in vivo antitumor efficacy.,Goswami R, Mukherjee S, Ghadiyaram C, Wohlfahrt G, Sistla RK, Nagaraj J, Satyam LK, Subbarao K, Palakurthy RK, Gopinath S, Krishnamurthy NR, Ikonen T, Moilanen A, Subramanya HS, Kallio P, Ramachandra M Bioorg Med Chem. 2014 Jun 15;22(12):3187-203. doi: 10.1016/j.bmc.2014.04.013., Epub 2014 Apr 18. PMID:24794746[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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