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Effect of IN-1130, a Small Molecule Inhibitor of Transforming Growth Factor-Beta Type I receptor/activin Receptor-Like kinase-5, on Prostate Cancer Cells

Effect of IN-1130, a Small Molecule Inhibitor of Transforming Growth Factor-Beta Type I receptor/activin Receptor-Like kinase-5, on Prostate Cancer Cells

Geun Taek Lee, Jun Hyuk Hong, Thomas J Mueller, John A Watson, Cheol Kwak, Youn Young Sheen, Dae-Kee Kim, Seong Jin Kim, Isaac Yi Kim

J Urol. 2008 Dec;180(6):2660-7.

PMID: 18951571

Abstract:

Purpose:
Transforming growth factor-beta is a potent immune suppressor that is over expressed by most malignant cells to evade the host immune response. Thus, a potential anticancer therapeutic strategy is the inhibition of transforming growth factor-beta signaling.
Materials and methods:
We investigated the specificity and the antitumor effect of IN-1130, a novel small molecule inhibitor of the transforming growth factor-beta type I receptor ALK-5.
Results:
IN-1130 inhibited transforming growth factor-beta induced cell death and gene transcriptional activity in a concentration dependent manner in the human hepatoma cell line HepG2. Simultaneously immunoblot analysis demonstrated that IN-1130 inhibited the Smad2 phosphorylation induced by transforming growth factor-beta. To determine the specificity of IN-1130 for transforming growth factor-beta signaling the effect on active and bone morphogenic protein signaling was subsequently investigated. Results demonstrated that IN-1130 did not inhibit bone morphogenic protein signaling. However, active signaling was blocked by IN-1130 in a concentration dependent manner. Furthermore, immunoblot analysis for phospho-Smad2 following transfection with constitutively active ALK-1 to 7 demonstrated that IN-1130 inhibited ALK-4 (active receptor type IB), 5 (TbetaRI) and 7 (nodal type I receptor). To investigate the antitumor effect of IN-1130 WT mice were injected subcutaneously with the murine prostate cancer cell line Tramp C2. Seven days later IN-1130 was administered intraperitoneally daily for 30 days. Results demonstrated a dramatic decrease in tumor volume in association with an enhanced immune response in the treatment group.
Conclusions:
Taken together these results demonstrate that IN-1130 is a relatively nontoxic inhibitor of ALK-4/5/7 that may potentially treat prostate cancer.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP868612833	IN-1130		868612-83-3	Price

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