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ELF_KLK6_Manuscript.pdf (1.09 MB)
Synthesis and Structure–Activity Relationships of N-(4-Benzamidino)-Oxazolidinones–Potent and Selective Inhibitors of Kallikrein-Related Peptidase 6
Preprints are manuscripts made publicly available before they have been submitted for formal peer review and publication. They might contain new research findings or data. Preprints can be a draft or final version of an author's research but must not have been accepted for publication at the time of submission.
submitted on 13.09.2019 and posted on 16.09.2019by Elena De Vita, Niels Smits, Helma van den Hurk, Elizabeth M. Beck, Joanne Hewitt, Gemma Baillie, Emily Russell, Andrew Pannifer, Véronique Hamon, Angus Morrison, Stuart P. McElroy, Philip Jones, Natalia A. Ignatenko, Nikolas Gunkel, Aubry K. Miller
Kallikrein-related peptidase 6 (KLK6) is a secreted
serine protease that belongs to the family of tissue kallikreins. Aberrant
expression of KLK6 has been found in different cancers and neurodegenerative
diseases, and KLK6 is currently studied as a potential target in these pathologies.
We report a novel series of KLK6 inhibitors discovered in a high-throughput
screen within the European Lead Factory program. Structure-guided design based
on docking studies enabled rapid progression of a hit cluster to inhibitors
with improved potency, selectivity and pharmacokinetic properties. In
particular, inhibitors 32 and 34 have single digit nanomolar potency
against KLK6, with over 25-fold and 100-fold selectivity, respectively, against
the closely related enzyme trypsin. The most potent compound, 32, effectively reduces KLK6-dependent
invasion of HCT116 cells. The high potency in combination with good solubility
and low clearance of 32 make it a
good chemical probe for KLK6 target validation in vitro and potentially in