The first potent diphenyl phosphonate KLK4 inhibitors with unexpected binding kinetics

Jeroen van Soom; Giuliana Cuzzucoli Crucitti; Rafaela Gladysz; Pieter van der Veken; Roberto Di Santo; Ingmar Stuyver; Victoria Buck; Anne-Marie Lambeir; Viktor Magdolen; Jurgen Joossens; Koen Augustyns

doi:10.1039/C5MD00288E

The first potent diphenyl phosphonate KLK4 inhibitors with unexpected binding kinetics†

Jeroen van Soom,‡^a Giuliana Cuzzucoli Crucitti,^ab Rafaela Gladysz,^a Pieter van der Veken,^a Roberto Di Santo,^b Ingmar Stuyver,^a Victoria Buck,^c Anne-Marie Lambeir,^d Viktor Magdolen,^c Jurgen Joossens^a and Koen Augustyns

*^a

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* Corresponding authors

^a Medicinal Chemistry (UAMC), Department of Pharmaceutical Sciences, University of Antwerp (UA), Universiteitsplein 1, B-2610 Antwerp, Belgium
E-mail: koen.augustyns@uantwerpen.be

^b Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur-Fondazione Cenci Bolognetti, “Sapienza” Università di Roma, P.le Aldo Moro 5, Roma I-00185, Italy

^c Klinische Forschergruppe der Frauenklinik, Klinikum rechts der Isar der TU München, Ismaninger Strasse 22, 81675 München, Germany

^d Medical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp (UA), Universiteitsplein 1, B-2610 Antwerp, Belgium

Abstract

KLK4 is a serine protease from the kallikrein family that is involved in cancer progression. The diphenyl phosphonate warhead is intended to bind irreversibly with serine proteases, but unexpectedly, very potent KLK4 diphenyl phosphonate inhibitors were discovered with reversible inhibition kinetics.

MedChemComm

The first potent diphenyl phosphonate KLK4 inhibitors with unexpected binding kinetics†

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The first potent diphenyl phosphonate KLK4 inhibitors with unexpected binding kinetics

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