Thursday, February 6, 2014
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Proprotein convertase subtilisin/kexin type 9 (PCSK9);
lipoprotein receptor (LDLR)
In vitro studies identified truncated analogs of the
epidermal growth factor-like domain A (EGF-A) of LDLR that could aid the
design of oral therapeutics to lower cholesterol. PCSK9 binds EGF-A on LDLR,
inhibits receptor recycling and thus reduces removal of LDL from the blood.
In binding assays, a truncated analog of EGF-A bound PCSK9 with a Kd
of ~0.6 mM and inhibited its interaction with EGF-A with an IC50
of ~18 mM. In hepatocellular carcinoma cells, the truncated
analogs induced LDLR recycling with an EC50 of ~25 mM.
This study was performed in collaboration with Pfizer
Inc., whose next steps include improving potency and
Inc.'s evolocumab, Regeneron
Pharmaceuticals Inc. and Sanofi's
alirocumab and Pfizer's bococizumab
are mAbs targeting PCSK9, and all are in Phase III testing to treat lipid
At least seven additional companies have PCSK9 inhibitors in clinical or
preclinical development (see PCSK9 peptide inhibitors, page 4).
Published online Feb. 6, 2014
Patent status undisclosed;
licensed to Pfizer; unavailable for licensing
Schroeder, C.I. et al.
Chem. Biol.; published online Jan. 16, 2014;
Contact: David J. Craik, The University of Queensland,
Brisbane, Queensland, Australia
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