ABT-888 shows a preferential activity on those MSI cell lines harboring mutations in both MRE11 and RAD50 genes compared to MSS cell lines (wild-type for both genes). A significant correlation exists between MRE11 expression levels and cytotoxicity to ABT-888 at 10 µM. Flow cytometry analyses show a G1 arrest following to the treatment with ABT-888 that is higher in MSI cell lines with mutations in MRE11 and RAD50 compared to MSS cell lines. ABT-888, this parp inhibitor, induces a pronounced reduction in PAR proteins in tumor samples and this ability of ABT-888 to rapidly inhibit PARP in vivo confirms its favorable pharmacokinetic profile. The preclinical pharmacokinetic studies predicate that ABT-888 will have good human bioavailability suitable for either once or twice daily dosing that can be combined with cytotoxic agents[1].

     SB-431542 is a selective inhibitor of endogenous activin and TGF-ß signaling but has no effect on BMP signaling. To demonstrate the specificity of SB-431542, we tested its effect on several other signal transduction pathways whose activities depend on the concerted activation of multiple kinases. SB-431542 has no effect on components of the ERK, JNK, or p38 MAP kinase pathways.SB-431542 inhibits TGF-ß-induced apoptosis and growth suppression in several cell types. SB-431542 efficiently blocks the tumor-promoting effects of TGF-ß including cell motility, migration, invasion, and vascular endothelial growth factor secretion in human cancer cell lines. SB-431542 increases the anchorage-independent growth of lung adenocarcinoma cells that are responsive to TGF-ß-induced growth inhibition. SB-431542 induces anchorage-independent growth of A549 cells as evident from both colony number and size in the soft agar assay. In contrast, SB-431542 dramatically suppressed the colony growth of HT29 cells. However, SB-431542 has no effect on colony formation in the case of VMRC-LCD cells that are not responsive to TGF-ß due to lack of TßRII expression[2].SB-431542 to selectively inhibit ALK-5 signaling but observed an inhibitory effect of SB-431542 on ligand-induced ALK-1 signaling in MG63 cells. Inman et al. reported that this inhibitor was not effective on the constitutively active form of ALK-1 in which Gln-201 was mutated to Asp. There appears to be two possible explanations for this observation. One is that SB-431542 has differential effects on ligand-activated ALK-1 kinase and mutationally activated ALK-1 kinase. SB-431542 can inhibit TGF-ß–mediated activation of SMAD2 and induction of fibronectin and collagen expression in TGF-ß–response cell lines.A recent report showed that SB-431542 blocked TGF-ß–mediated increase in proliferation in a mesenchymal cell line. This compound can block activation of SMAD2 and induction of extracellular matrix components by TGF-ß in TGF-ß–responsive cells. SB-431542 inhibited TGF-ß–mediated c-myc expression and the proliferation of osteosarcoma cell line that is growth stimulated in response to TGF-ß. Less clear are the effects of SB-431542 on the TGF-ß signaling and phenotypic changes on epithelial cancer cells that have disruption of normal TGF-ß responses.[3]

References

[1] Cherrie K. Donawho,et al. Clin Cancer Res May 1, 2007 13; 2728

[2] Sunil K Halder,et al. Neoplasia. 2005 May; 7(5): 509–521.

[3] Mark D. Hjelmeland,et al. Mol Cancer Ther June 2004 3; 737
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