Rational Design of Autotaxin Inhibitors by Structural Evolution of Endogenous Modulators.
Autotaxin produces the bioactive lipid lysophosphatidic acid (LPA) and is a drug target of considerable interest for numerous pathologies. We report the expedient, structure-guided evolution of weak physiological allosteric inhibitors (bile salts) into potent competitive Autotaxin inhibitors that do not interact with the catalytic site. Functional data confirms that our lead compound attenuates LPA mediated signaling in cells and reduces LPA synthesis in vivo, providing a promising natural product derived scaffold for drug discovery.
Division of Biochemistry, The Netherlands Cancer Institute , Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.
Willem-Jan
WJ
Keune
Department of Pure and Applied Chemistry, University of Strathclyde , 295 Cathedral Street, Glasgow, G1 1XL, U.K.
Frances
F
Potjewyd
Division of Biochemistry, The Netherlands Cancer Institute , Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.
Tatjana
T
Heidebrecht
Division of Biochemistry, The Netherlands Cancer Institute , Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.
Fernando
F
Salgado-Polo
GlaxoSmithKline R&D , Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
Simon J F
0000-0002-4859-8246
SJ
Macdonald
Division of Cardiovascular Medicine and the Gill Heart Institute, Lexington Veterans Affairs Medical Center , Lexington Kentucky 40536, United States.
Lakshman
L
Chelvarajan
Division of Cardiovascular Medicine and the Gill Heart Institute, Lexington Veterans Affairs Medical Center , Lexington Kentucky 40536, United States.
Ahmed
A
Abdel Latif
Division of Cardiovascular Medicine and the Gill Heart Institute, Lexington Veterans Affairs Medical Center , Lexington Kentucky 40536, United States.
Sony
S
Soman
Division of Cardiovascular Medicine and the Gill Heart Institute, Lexington Veterans Affairs Medical Center , Lexington Kentucky 40536, United States.
Andrew J
AJ
Morris
Department of Pure and Applied Chemistry, University of Strathclyde , 295 Cathedral Street, Glasgow, G1 1XL, U.K.
Allan J B
0000-0002-1582-4286
AJ
Watson
Department of Pure and Applied Chemistry, University of Strathclyde , 295 Cathedral Street, Glasgow, G1 1XL, U.K.
Craig
0000-0002-6567-8272
C
Jamieson
Division of Biochemistry, The Netherlands Cancer Institute , Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.
Anastassis
A
Perrakis
D000494:Allosteric Regulation; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D003460:Crystallization; D013058:Mass Spectrometry; D015394:Molecular Structure; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects*; D066244:Proton Magnetic Resonance Spectroscopy; D000099189:Lysophospholipase D
D010727:Phosphoric Diester Hydrolases; D000099189:Lysophospholipase D