Synthesis and biological evaluation of phosphonate derivatives as autotaxin (ATX) inhibitors

Abstract

Autotaxin (ATX) is an autocrine motility factor that promotes cancer cell invasion, cell migration and angiogenesis. ATX, originally discovered as a nucleotide phosphodiesterase, is known now to be responsible for the lysophospholipid-preferring phospholipase D activity in plasma. As such, it catalyzes the production of lysophosphatidic acid (LPA) from lysophophatidylcholine (LPC). ATX is thus an attractive drug target; small molecular inhibitors might be efficacious in slowing the spread of cancers. With this study we have generated a series of beta-keto and beta-hydroxy phosphonate derivatives of LPA, some of which are potent ATX inhibitors. KeywordsAutotaxin; ATX; Phosphonate; Choline; LPA The autocrine motility factor autotaxin (ATX) was originally isolated from melanoma cell supernatants as a 125-kD glycoprotein that stimulated tumor cell motility. 1 In vivo experiments documented that forced expression of ATX augments tumor cell invasion and metastasis. 2 Further, ATX promotes angiogenesis and may act in concert with other angiogenic factors to facilitate new blood vessel formation. 3 These biological properties require enzymatic activity.ATX belongs to the nucleotide pyrophosphatase and phosphodiesterase (NPP) family of enzymes, which hydrolyze phosphodiester and diphosphate bonds, typically found in ATP and ADP. 4 Interest in ATX was stimulated by the identification of this enzyme as the long elusive plasma lysophospholipase D activity, which is responsible for the cleavage of choline group of lysophophatidylcholine (LPC) to form lysophosphatidic acid (LPA) ( Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript 1). 5,6 This is a major pathway of biosynthesis of LPA in plasma. 7,8 LPA is an intercellular lipid mediator that influences many biochemical processes including cell proliferation, smooth muscle contraction, platelet aggregation and apoptosis. [9][10][11] For example, LPA is the "ovarian cancer activating factor" in ascitic fluid characteristic of ovarian cancer patients. Elevated levels of LPA are present both at early and late stages in ovarian cancer and may play a role in tumor cell proliferation and invasion. 12,13 LPA mediates its effects through the activation of G protein-coupled receptors (GPCR). 14 Thus, great efforts have been made on the study of LPA receptor antagonists and agonists due to their therapeutic potential. [15][16][17][18][19][20][21] In aggregate, these data suggest that ATX is an attractive pharmacological target; blockage of LPA produ...

Autotaxin protects MCF-7 breast cancer and MDA-MB-435 melanoma cells against Taxol-induced apoptosis

“…However, in our work, LPC alone did not antagonize Taxolinduced apoptosis unless concentrated medium from MDA-MB-435 cells or recombinant ATX was added. This protective effect was blocked by VPC8a202 and S32826, two ATX inhibitors (Cui et al, 2007;Ferry et al, 2008), or by heat inactivation of ATX activity. The MDA-MB-435 medium, compared with that produced by MCF-7 cells, contained abundant ATX.…”

“…We also used an ATX inhibitor, VPC8a202 (Cui et al, 2007), to determine whether the effect of concentrated medium depended upon ATX activity. VPC8a202 (1 mM) decreased ATX activity by 87% as expected (results not shown) and it abolished the protective effect of LPC plus concentrated media from MDA-MB-435 cells (Figure 4a).…”

Regulation of autotaxin expression and secretion by lysophosphatidate and sphingosine 1-phosphate

“…This work is based mainly on studies where ATX activity was measured with very low concentrations (1-5 M) of fl uorescent LPC-analog substrates ( 18,19 ). This technique was also used to identify LPA analogs as possible ATX inhibitors (20)(21)(22)(23).…”

Autotaxin – A Target for the Treatment of Drug-Resistant Ovarian Cancer?

“…In this section we have concentrated on recent reports of small molecule inhibitors of autotaxin. Cui and Macdonald have developed a series of tyrosine-derived -hydroxyphosphonates as analogues of LPA that display activity as inhibitors of autotaxin (Cui et al 2007;Cui et al 2008). The synthesis of this series of compounds is highlighted in Figure 3.…”

“…The sodium borohydride reduction step gave rise to a mixture of two diasteroisomeric products that were separated and isolated by column chromatography. In the initial publications (Cui et al 2007;Cui et al 2008) the relative stereochemistry at the new chiral centre had not been determined, but later work from this group on a more advanced series of inhibitors gave insight to the relationship between stereochemistry and activity in the lead compounds (East et al 2010). From an initial series of targets prepared (R 1 = C 15 H 31 , variation of R 2 ), the most active compound to be identified was compound 1a, derived from S-tyrosine and later confirmed to have the relative stereochemistry shown (Fig.…”