Identification of a novel class of autotaxin inhibitors through cross-screening

Abstract

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

The Problem with Problems: Fundamental to Applied Research Using Palladium

“…Despite this, we were successful in developing a novel LPA 1 antagonist scaffold, 15, which displayed moderate potency ( Figure 2). 36 However, this was as far as the LPA 1 story progressed. Throughout the process we learned a great deal from a scientific perspective -in both areas -and, from a personal viewpoint, learning to let go of a project was certainly valuable.…”

Molecular modelling guided design, synthesis and QSAR analysis of new small molecule non-lipid autotaxin inhibitors

“…ENPP2), which is responsible for catalyzing the hydrolysis of lysophosphatidyl choline (LPC) and similar lysophospholipids to a growth-factor like bioactive phospholipid, lysophosphatidic acid (LPA). [1][2][3][4][5][6][7][8][9][10][11][12][13] On the cell surface, LPA acts via six membrane-bound G-protein coupled receptors, LPAR 1-6 (LPAR), to promote a variety of physiological responses, including cell proliferation, migration, motility, survival, and platelet aggregation. 6,7,[13][14][15] Thus, the ATX-LPA signaling pathway has been considered to be at the core of a number of diseases, including fibrotic diseases, cardiovascular diseases, inflammation, and central pain.…”

“…[1][2][3][4][5][6][7][8][9][10][11][12][13] On the cell surface, LPA acts via six membrane-bound G-protein coupled receptors, LPAR 1-6 (LPAR), to promote a variety of physiological responses, including cell proliferation, migration, motility, survival, and platelet aggregation. 6,7,[13][14][15] Thus, the ATX-LPA signaling pathway has been considered to be at the core of a number of diseases, including fibrotic diseases, cardiovascular diseases, inflammation, and central pain. 6,7,10,13,16,17 In cancer cell biology, the ATX-LPA axis has been found to regulate malignant transformation, invasion, metastasis, and therapeutic resistance.…”

“…6,7,[13][14][15] Thus, the ATX-LPA signaling pathway has been considered to be at the core of a number of diseases, including fibrotic diseases, cardiovascular diseases, inflammation, and central pain. 6,7,10,13,16,17 In cancer cell biology, the ATX-LPA axis has been found to regulate malignant transformation, invasion, metastasis, and therapeutic resistance. 1,4,6,10,13,[18][19][20][21] Additionally, ATX has been observed to play a critical role in proliferation and survival of ovarian cancer as well as breast cancer stem cells.…”

“…As the product of ATX is LPA, which activates six LPA GPCR, there is widespread interest in finding non-lipid small molecule antagonists of both ATX and LPAR. 7,19 One might expect that dual inhibitors of ATX and LPARs would be more effective in overcoming LPA mediated resistance to chemotherapy and radiation therapy. Previously, we have reported a lipid-like pan LPAR antagonist (Brp-LPA, Figure 1), which is a nanomolar inhibitor of ATX as well.…”