Optimization of a pipemidic acid autotaxin inhibitor.
Autotaxin (ATX, NPP2) has recently been shown to be the lysophospholipase D responsible for synthesis of the bioactive lipid lysophosphatidic acid (LPA). LPA has a well-established role in cancer, and the production of LPA is consistent with the cancer-promoting actions of ATX. Increased ATX and LPA receptor expression have been found in numerous cancer cell types. The current study has combined ligand-based computational approaches (binary quantitative structure-activity relationship), medicinal chemistry, and experimental enzymatic assays to optimize a previously identified small molecule ATX inhibitor, H2L 7905958 (1). Seventy prospective analogs were analyzed via computational screening, from which 30 promising compounds were synthesized and screened to assess efficacy, potency, and mechanism of inhibition. This approach has identified four analogs as potent as or more potent than the lead. The most potent analog displayed an IC(50) of 900 nM with respect to ATX-mediated FS-3 hydrolysis with a K(i) of 700 nM, making this compound approximately 3-fold more potent than the previously described lead.
Hoeglund
Adrienne B
AB
Department of Chemistry, The University of Memphis, Memphis, Tennessee 38152, USA.
Bostic
Heidi E
HE
Howard
Angela L
AL
Wanjala
Irene W
IW
Best
Michael D
MD
Baker
Daniel L
DL
Parrill
Abby L
AL
D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D017076:Computer-Aided Design; D004353:Drug Evaluation, Preclinical; D057075:Enzyme Assays; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008244:Lysophosphatidylcholines / Q000378:metabolism; D008246:Lysophospholipids / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000737:chemistry* / Q000378:metabolism*; D043264:Phosphodiesterase I / Q000737:chemistry* / Q000378:metabolism*; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry / Q000378:metabolism; D010876:Pipemidic Acid / Q000737:chemistry*; D011755:Pyrophosphatases / Q000737:chemistry* / Q000378:metabolism*; D021281:Quantitative Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D000099189:Lysophospholipase D
D004791:Enzyme Inhibitors; D008244:Lysophosphatidylcholines; D008246:Lysophospholipids; D009097:Multienzyme Complexes; D043264:Phosphodiesterase I; D010727:Phosphoric Diester Hydrolases; D010876:Pipemidic Acid; D011755:Pyrophosphatases; D000099189:Lysophospholipase D; C502079:ENPP6 protein, human; C032881:lysophosphatidic acid