KP-457

KP-457 is a selective a disintegrin and metalloproteinase 17 (ADAM17) inhibitor, with higher selectivity for ADAM17 than for other MMPs and ADAM10, and 5050s are 11.1 nM (ADAM17), 748 nM (ADAM10), 717 nM (MMP2), 9760 nM (MMP3), 2200 nM (MMP8), 5410 nM (MMP9), 930 nM (MMP13), 2140 nM (MMP14), and 7100 nM (MMP17), respectively.

Signaling Pathways >> Metabolic Enzyme/Protease >> MMP

Research Areas >> Cardiovascular Disease

ADAM17:11.1 nM (IC50)

ADAM10:748 nM (IC50)

MMP2:717 nM (IC50)

MMP13:930 nM (IC50)

MMP14:2140 nM (IC50)

MMP8:2200 nM (IC50)

MMP9:5410 nM (IC50)

MMP17:7100 nM (IC50)

MMP3:9760 nM (IC50)

KP-457 is a selective metalloproteinase 17 (ADAM17) inhibitor, with higher selectivity for ADAM17 than for other MMPs and ADAM10, and IC50s are 11.1 nM (ADAM17), 748 nM (ADAM10), 717 nM (MMP2), 9760 nM (MMP3), 2200 nM (MMP8), 5410 nM (MMP9), 930 nM (MMP13), 2140 nM (MMP14), and 7100 nM (MMP17), respectively. KP-457 blocks Zn2+ chelation of the catalytic domain of ADAM17. KP-457 (15 μM) retains the expression of GPIbα on iPSC-derived platelets[1].

In a thrombus formation model using immunodeficient mice after platelet transfusion, induced pluripotent stem cells (iPSCs) platelets generated with KP-457 exerts good hemostatic function[1].

Briefly, 3 × 104 hematopoietic progenitor cells (HPCs) derived from iPS-sacs on C3H10T1/2 feeder cells in the presence of 20 ng/mL vascular endothelial growth factor are transferred on day 14 of culture onto C3H10T1/2 feeder cells in differentiation medium supplemented with 50 ng/mL stem cell factor, 100 ng/mL thrombopoietin, 25 U/mL heparin sodium, and KP-457 at 24°C or 37°C. The medium is refreshed every 3 days, and nonadherent cells are collected and analyzed on days 22-24[1].

[1]. Hirata S, et al. Selective Inhibition of ADAM17 Efficiently Mediates Glycoprotein Ibα Retention During Ex Vivo Generation of Human Induced Pluripotent Stem Cell-Derived Platelets. Stem Cells Transl Med. 2017 Mar;6(3):720-730.

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