IPR-803

IPR-803 (CAS No. 892243-35-5) is a small-molecule competitive inhibitor targeting the urokinase receptor uPAR. It exerts its core function by specifically binding to uPAR and blocking its protein–protein interaction with urokinase-type plasminogen activator uPA. The meta-carboxyl group in the molecule is an essential moiety for binding the key uPAR residue Arg53 and maintaining inhibitory activity. Biochemical assays confirmed an IC₅₀=10 μM for inhibition of uPAR-uPA binding, and it can block the uPAR–uPA interaction in a concentration-dependent manner. In cell-based experiments, this compound is mainly used for in vitro studies in breast cancer MDA-MB-231 cells and pancreatic cancer cells. Within the 25–200 μM concentration range, it can significantly inhibit tumor cell invasion, reduce uPA expression, downregulate the p-ERK signaling pathway, and inhibit angiogenesis; it has some inhibitory effect on cell proliferation, and does not affect cell migration or adhesion.

In animal experiments, IPR-803 is mainly used for treatment in mouse tumor models: in an orthotopic breast cancer lung metastasis model (NSG/NOD-SCID mice), oral administration at 200 mg/kg can significantly inhibit breast cancer lung metastasis; when loaded as a uPA inhibitor into a pH-responsive nanomedicine, intravenous tail-vein injection at 10 mg/kg for treatment in a pancreatic cancer subcutaneous xenograft mouse model can loosen the tumor stroma, inhibit tumor angiogenesis, and enhance the antitumor efficacy of gemcitabine, with no obvious systemic toxic side effects observed at the above treatment doses.

References:

[1] Khanna M, Wang F, Jo I, Knabe WE, Wilson SM, Li L, Bum-Erdene K, Li J, W Sledge G, Khanna R, Meroueh SO. Targeting multiple conformations leads to small molecule inhibitors of the uPAR·uPA protein-protein interaction that block cancer cell invasion. ACS Chem Biol. 2011 Nov 18;6(11):1232-43. doi: 10.1021/cb200180m. Epub 2011 Sep 29. PMID: 21875078; PMCID: PMC3220747.

[2] Mani T, Wang F, Knabe WE, Sinn AL, Khanna M, Jo I, Sandusky GE, Sledge GW Jr, Jones DR, Khanna R, Pollok KE, Meroueh SO. Small-molecule inhibition of the uPAR·uPA interaction: synthesis, biochemical, cellular, in vivo pharmacokinetics and efficacy studies in breast cancer metastasis. Bioorg Med Chem. 2013 Apr 1;21(7):2145-55. doi: 10.1016/j.bmc.2012.12.047. Epub 2013 Jan 9. PMID: 23411397; PMCID: PMC3625246.

[3] Fu N, Qin K, Li D, Zhu M, Jiang Y, Liu W, Jin J. Stromal homeostasis-restoring "rocket-like" nanomedicine inhibited pancreatic tumor growth in vivo. Mater Today Bio. 2026 Mar 27;38:103014. doi: 10.1016/j.mtbio.2026.103014. PMID: 42006710; PMCID: PMC13091541.