KP-457

KP‐457 is a selective ADAM17 inhibitor, which has a reverse-hydroxamate structure. ADAM17, also known as TNF-α-converting enzyme, cleaves various molecules such as GPIbα, GPV, and TNF-α. KP‐457 inhibited cleavages of the TNF‐α sequence with 10 times the potency of GM‐6001 and was >50 times more selective for ADAM17 than for other MMPs and ADAM10 in cell‐free enzyme assays.^[1]

The inhibition of C-terminal cleavage of the GPIbα sequence by ADAM17 was concentration dependent, with an IC50 of 10.6 nmol/l for KP-457. KP-457 at the lower concentration blocks Zn2+ chelation of the catalytic domain of ADAM17. Other studies confirmed that KP-457 exhibited neither genotoxicity nor systemic toxicity at doses up to 3 mg/kg administered to dogs intravenously once a day for 1 month. In vitro study also demonstrated that KP-457 could sustain intact GPIbα at levels seen in platelets freshly isolated from human blood. In addition, KP-457 inhibited GPIbα shedding with a potency 10 times that of GM-6001 in the cellular assay.^[1]

References:
[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.