Autotaxin (ATX) is a secreted enzyme responsible for the hydrolysis of lysophosphatidylcholine (LPC) to the bioactive lysophosphatidic acid (LPA) and choline. The ATX-LPA signaling pathway is implicated in cell survival, migration, and proliferation; thus, the inhibition of ATX is a recognized therapeutic target for a number of diseases including fibrotic diseases, cancer, and inflammation, among others. Many of the developed synthetic inhibitors for ATX have resembled the lipid chemotype of the native ligand; however, a small number of inhibitors have been described that deviate from this common scaffold. Herein, we report the structure-activity relationships (SAR) of a previously reported small molecule ATX inhibitor. We show through enzyme kinetics studies that analogues of this chemotype are noncompetitive inhibitors, and by using a crystal structure with ATX we confirm the discrete binding mode.
the pharmacological effects of the extracts from A. cominia observed in experimental diabetic models were shown in this study. A. cominia is potentially a new candidate for the treatment and management of T2-DM.
BackgroundEthno-botanical information from diabetic patients in Cuba led to the identification of Allophylus cominia as a possible source of new drugs for the treatment of type 2 diabetes mellitus (T2-DM).
ExperimentalChemical characterization of the extracts from A. cominia was carried out using chromatographic and spectroscopic methods. The extracts were tested for their activity on PTP1B, DPPIV, α-glucosidase enzymes and α-amylase.
ResultsThe flavonoid rich fractions from A. cominia inhibited DPPIV enzyme (75.3±2.33%) at 30 µg/ml and produced a concentration-dependent inhibition against DPPIV with a Ki value of 2.6 µg/ml. At 30 µg/ml, flavonoids and pheophytins extracts significantly inhibited PTP1B enzyme (100±2.6% and 68±1% respectively). The flavonoids, pheophytin A and pheophytin B fractions showed significant concentration-dependent inhibition against PTP1Bwith Ki values of 3 µg/ml, 0.64 µg/ml and 0.88 µg/ml respectively. At 30 µg/ml, the flavonoid fraction significantly inhibited α-glucosidase enzyme (86±0.3%) in a concentration-dependent pattern with a Ki value of 2 µg/ml.None of the fractions showed significant effects on α-amylase. Fatty acids, tannins, pheophytins A and B, and a mixture of flavonoids were detected in the methanolic extract from A. cominia. The identified flavonoids were mearnsitrin, quercitrin, quercetin-3-alloside, and naringenin-7-glucoside.
Three novel series were generated in order to mimic the pharmacophoric features displayed by lead compound AM095, a Lysophosphatidic acid (LPA1) receptor antagonist. Biological evaluation of this array of putative LPA1 antagonists led us to the discovery of three novel series of inhibitors of the ecto-enzyme Autotaxin (ATX), responsible for LPA production in blood, with potencies in the range 1 – 4 μM accompanied with good (> 100 μg/mL) solubility
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