Details

Autor(en) / Beteiligte

• De Vita, Elena
• Smits, Niels
• Hurk, Helma
• Beck, Elizabeth M.
• Hewitt, Joanne
• Baillie, Gemma
• Russell, Emily
• Pannifer, Andrew
• Hamon, Véronique
• Morrison, Angus
• McElroy, Stuart P.
• Jones, Philip
• Ignatenko, Natalia A.
• Gunkel, Nikolas
• Miller, Aubry K.

Titel

Synthesis and Structure‐Activity Relationships of N‐(4‐Benzamidino)‐Oxazolidinones: Potent and Selective Inhibitors of Kallikrein‐Related Peptidase 6

Ist Teil von

• ChemMedChem, 2020-01, Vol.15 (1), p.79-95

Ort / Verlag

Germany: Wiley Subscription Services, Inc

Erscheinungsjahr

2020

Quelle

Wiley-Blackwell Full Collection

Beschreibungen/Notizen

• 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 ((5R)‐3‐(4‐carbamimidoylphenyl)‐N‐((S)‐1‐(naphthalen‐1‐yl)propyl)‐2‐oxooxazolidine‐5‐carboxamide) and 34 ((5R)‐3‐(6‐carbamimidoylpyridin‐3‐yl)‐N‐((1S)‐1‐(naphthalen‐1‐yl)propyl)‐2‐oxooxazolidine‐5‐carboxamide) have single‐digit nanomolar potency against KLK6, with over 25‐fold and 100‐fold selectivities against the closely related enzyme trypsin, respectively. 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 vivo. A successful screen performed within the European Lead Factory program, followed by docking studies, has resulted in compound 32, a potent and selective N‐(4‐benzamidino)‐oxazolidinone inhibitor of kallikrein‐related peptidase 6 (KLK6). Aberrant levels of this serine protease have been found in different malignancies and in neurodegenerative diseases. Good solubility and low clearance of 32 make it a good probe for KLK6 target validation.