PDBsum entry 5za9

Hydrolase

PDB id: 5za9

Contents

Protein chain

245 a.a.

Ligands

50I

Waters ×106

PDB id:

5za9

Name:

Hydrolase

Title:

Upa-bb2-50f

Structure:

Urokinase-type plasminogen activator chain b. Chain: u. Synonym: upa. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: plau. Expressed in: komagataella pastoris. Expression_system_taxid: 4922

Resolution:

1.62Å R-factor: 0.218 R-free: 0.236

Authors:

B.J.Buckley,L.G.Jiang,M.D.Huang,M.J.Kelso,M.Ranson

Key ref:

B.J.Buckley et al. (2018). 6-Substituted Hexamethylene Amiloride (HMA) Derivatives as Potent and Selective Inhibitors of the Human Urokinase Plasminogen Activator for Use in Cancer. J Med Chem, 61, 8299-8320. PubMed id: 30130401 DOI: 10.1021/acs.jmedchem.8b00838

Date:

07-Feb-18 Release date: 19-Dec-18

Protein chain

P00749  (UROK_HUMAN) -  Urokinase-type plasminogen activator from Homo sapiens

Seq: 431 a.a.

Struc: 245 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.3.4.21.73 - u-plasminogen activator.
• Reaction: Specific cleavage of Arg-|-Val bond in plasminogen to form plasmin.

DOI no: 10.1021/acs.jmedchem.8b00838

J Med Chem 61:8299-8320 (2018)

PubMed id: 30130401

6-Substituted Hexamethylene Amiloride (HMA) Derivatives as Potent and Selective Inhibitors of the Human Urokinase Plasminogen Activator for Use in Cancer.

B.J.Buckley, A.Aboelela, E.Minaei, L.X.Jiang, Z.Xu, U.Ali, K.Fildes, C.Y.Cheung, S.M.Cook, D.C.Johnson, D.A.Bachovchin, G.M.Cook, M.Apte, M.Huang, M.Ranson, M.J.Kelso.

ABSTRACT

Metastasis is the cause of death in the majority (∼90%) of malignant cancers. The oral potassium-sparing diuretic amiloride and its 5-substituted derivative 5 -N, N-(hexamethylene)amiloride (HMA) reportedly show robust antitumor/metastasis effects in multiple in vitro and animal models. These effects are likely due, at least in part, to inhibition of the urokinase plasminogen activator (uPA), a key protease determinant of cell invasiveness and metastasis. This study reports the discovery of 6-substituted HMA analogs that show nanomolar potency against uPA, high selectivity over related trypsin-like serine proteases, and minimal inhibitory effects against epithelial sodium channels (ENaC), the diuretic and antikaliuretic target of amiloride. Reductions in lung metastases were demonstrated for two analogs in a late-stage experimental mouse metastasis model, and one analog completely inhibited formation of liver metastases in an orthotopic xenograft mouse model of pancreatic cancer. The results support further evaluation of 6-substituted HMA derivatives as uPA-targeting anticancer drugs.