Products

P22077 is a potent and selective USP7 inhibitor. It specifically inhibits deubiquitylating enzyme (DUB) USP7

and the closely related USP47 (at 5µM), but not the other majority of DUBs (at 15-45µM). USP7 has been

found to be critical in cancer progression due to its influence on the stability of the tumor suppressor p53.

The inhibition of USP7 is predicted to destabilize HDM2 and stabilize p53, and USP7 exerts both p53-

dependent and p53-independent effects on controlling cell proliferation and apoptosis.

References

1. Mikael Altun et al. Activity-Based Chemical Proteomics Accelerates Inhibitor Development for

   Deubiquitylating Enzymes. (2011) Chemistry & Biology 18, 14011412.

Bortezomib is a first-in-class dipeptide boronic acid-based, water-soluble proteasome inhibitor. As a single

agent, bortezomib was found to have consistent antitumor activity in both chemosensitive and

chemoresistant multiple myeloma cells at an IC50 of 10-20 ng/mL. [1] Bortezomib overcomes the resistance

to apoptosis in multiple myeloma cells that is induced by IL-6. [2] Additionally, bortezomib prevents TNF-a-

induced, NF-kB-dependent upregulation of IL-6 and reduces cell adhesion; proliferation of remaining

adherent multiple myeloma cells was also inhibited by bortezomib. [1]

In MM cell lines U266, IM-9, and Hs Sultan, bortezomib inhibited at IC50 concentrations of 3, 6, and 20 nM,

respectively. [2] Cell growth of Dox40, MR20, and LR5 MM cells was completely inhibited by bortezomib at

100 nM IC50.

Bortezomib suppresses growth and induces apoptosis in Bcr/Abl-positive cells sensitive and resistant to IM.

nterestingly, sequential combination of bortezomib followed by imatinib resulted in a synergistic pro-

apoptotic effect in imatinib-resistant cells; simultaneous exposure of bortezomib and imatinib was

antagonistic. [3]

References

1. Richardson et al., Cancer Control, 2003, 10(6), 361-369.

2. Hideshima et al., The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes

   drug resistance in human multiple myeloma cells. Cancer Res. 2001, 61, 3071-3076. Pubmed ID: 1306489

3. Gatto et al., The proteasome inhibitor PS-341 inhibits growth and induces apoptosis in Bcr/Abl-positive

   cell lines sensitive and resistant to imatinib mesylate. Haematologica, 2003, 88(8), 853-863.

   Pubmed ID: 12935973

SU5416 (Semaxinib) is a reversible, ATP-competitive, oxindole-based inhibitor of Flk-1/KDR receptor tyrosine

kinase. SU5416 inhibits VEGF-dependent phosphorylation of the Flk-1 receptor in Flk-1-overexpressing NIH

3T3 cells with a IC50 of 1.04 uM. In an ELISA-based assay, SU5416 inhibits autophosphorylation of the Flk-1

receptor at an IC50 of 1.23 uM. [1]

In a mitogenic/proliferation assay in HUVECs, the IC50 of SU5416 is extremely time-dependent, ranging from

1 uM to 40 nM at 48h incubation. These data in conjunction with dose-ranging studies support regimens of

less than once-daily dosing of SU5416. [2]

More recent studies have shown that SU5416 is also an agonist of the aryl hydrocarbon receptor (AHR),

leading to the generation of regulatory T-cells in vitro. SU5416 also upregulates CYP1A1 and CYP1B1. [3]

References

1. Fong et al., SU5416 Is a Potent and Selective Inhibitor of the Vascular Endothelial Growth Factor Receptor

   (Flk-1/KDR) That Inhibits Tyrosine Kinase Catalysis, Tumor Vascularization, and Growth of Multiple Tumor

   Types. Cancer Res. 1999, 59, 99-106. Pubmed ID: 9892193

2. Mendel et al., The Angiogenesis Inhibitor SU5416 Has Long-lasting Effects on Vascular Endothelial Growth

   Factor Receptor Phosphorylation and Function. Clin. Cancer Res. 2000, 6, 4848-4858. Pubmed ID: 11156244  

3. Mezrich et al., SU5416, a VEGF Receptor Inhibitor and Ligand of the AHR, Represents a New Alternative for

   Immunomodulation. PLOS One, 2012, 7(9), e44547.