MetAP-2, a cytoplasmic metalase, catalyzes the hydrolysis and removal of N-terminal methionine residues from newborn proteins. The enzymatic activity of MetAP-2 is a prerequisite for biological processes such as activity, subcellular localization, and protein stability. Importantly, it is involved in tissue repair and protein degradation, especially in angiogenesis and the growth of new blood vessels. Rheumatoid arthritis (RA) is a chronic inflammatory disease that progressively destroys joints, accompanied by aggressive synovial hyperplasia and neovascularization. Meanwhile, MetAP-2 is highly expressed in germinal center B cells and germinal center-derived non-Hodgkin’s lymphomas (NHL). Thus, MetAP-2 has become an effective target for diseases including solid tumor cancer and rheumatoid arthritis. Here, we will introduce an irreversible MetAP-2 inhibitor, PPI-2458.

PPI-2458 selectively and irreversibly inhibits MetAP-2, exerting anti-tumor and anti-inflammatory effects.

As in vitro studies demonstrated, PPI-2458 (100 nM; 5-6 d) completely inhibits MetAP-2 in different B-cell lymphomas. It (0.001-10 nM; 7 d or 4 d) significantly inhibits the proliferation of human fibroblast-like synovial cells (HFLS-RA) and human umbilical vein endothelial cells (HUVEC). It also decreases the intracellular protein level of PCNA, which is a functional platform for DNA processing and cell cycle regulation. Therefore, PPI-2458 blocks the cell cycle at the G1 phase.

As for in vivo activity, PPI-2458 (0.25, 1, 5, and 50 mg/kg; p.o.; every other day for 20 days) significantly reduces paw swelling after chronic disease attack in a peptidocan polysaccharide induced arthritis rat model. It (0.1, 0.3, 1, and 3 mg/kg; p.o.; every other day for 13 days) also consumes germinal center lymphocytes reversibly in cynomolgus monkeys, and the germinal center recovered within 3 weeks after agent withdrawal. It (10, 30, or 100 mg/kg; every other day for 20 days) also inhibits SR cell proliferation and tumor growth in vivo in the SR xenograft model. Of note, PPI-2458 (6 mg/kg, 60 mg/kg; i.v.; 14 days) shows less central nervous system toxicity than the parent compound TNP-470, and did not cause seizures in mice.

In a word, PPI-2458 is an ideal MetAP-2 inhibitor with oral activity. It has anti-angiogenesis, anti-inflammatory, and anti-tumor effects in vivo and in vitro.


[1] Bernier SG, et al. Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10768-73.

[2] Cooper AC, et al. Clin Cancer Res. 2006 Apr 15;12(8):2583-90.