title: Benzyl and naphthalene methylphosphonic acid inhibitors of autotaxin with anti-invasive and anti-metastatic activity.
abstract: Autotaxin (ATX, NPP2) is a member of the nucleotide pyrophosphate phosphodiesterase enzyme family. ATX catalyzes the hydrolytic cleavage of lysophosphatidylcholine (LPC) by lysophospholipase D activity, which leads to generation of the growth-factor-like lipid mediator lysophosphatidic acid (LPA). ATX is highly upregulated in metastatic and chemotherapy-resistant carcinomas and represents a potential target to mediate cancer invasion and metastasis. Herein we report the synthesis and pharmacological characterization of ATX inhibitors based on the 4-tetradecanoylaminobenzylphosphonic acid scaffold, which was previously found to lack sufficient stability in cellular systems. The new 4-substituted benzylphosphonic acid and 6-substituted naphthalen-2-ylmethylphosphonic acid analogues block ATX activity with K(i) values in the low micromolar to nanomolar range against FS3, LPC, and nucleotide substrates through a mixed-mode inhibition mechanism. None of the compounds tested inhibit the activity of related enzymes (NPP6 and NPP7). In addition, the compounds were evaluated as agonists or antagonists of seven LPA receptor (LPAR) subtypes. Analogues 22 and 30 b, the two most potent ATX inhibitors, inhibit the invasion of MM1 hepatoma cells across murine mesothelial and human vascular endothelial monolayers in vitro in a dose-dependent manner. The average terminal half-life for compound 22 is 10±5.4 h and it causes a long-lasting decrease in plasma LPA levels. Compounds 22 and 30 b significantly decrease lung metastasis of B16-F10 syngeneic mouse melanoma in a post-inoculation treatment paradigm. The 4-substituted benzylphosphonic acids and 6-substituted naphthalen-2-ylmethylphosphonic acids described herein represent new lead compounds that effectively inhibit the ATX-LPA-LPAR axis both in vitro and in vivo.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee, Health Science Center, Memphis, TN 38163, USA.
authors.forename: Renuka
authors.initials: R
authors.lastname: Gupte
authors.forename: Renukadevi
authors.initials: R
authors.lastname: Patil
authors.forename: Jianxiong
authors.initials: J
authors.lastname: Liu
authors.forename: Yaohong
authors.initials: Y
authors.lastname: Wang
authors.forename: Sue C
authors.initials: SC
authors.lastname: Lee
authors.forename: Yuko
authors.initials: Y
authors.lastname: Fujiwara
authors.forename: James
authors.initials: J
authors.lastname: Fells
authors.forename: Alyssa L
authors.initials: AL
authors.lastname: Bolen
authors.forename: Karin
authors.initials: K
authors.lastname: Emmons-Thompson
authors.forename: C Ryan
authors.initials: CR
authors.lastname: Yates
authors.forename: Anjaih
authors.initials: A
authors.lastname: Siddam
authors.forename: Nattapon
authors.initials: N
authors.lastname: Panupinthu
authors.forename: Truc-Chi T
authors.initials: TC
authors.lastname: Pham
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Baker
authors.forename: Abby L
authors.initials: AL
authors.lastname: Parrill
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.forename: Gabor
authors.initials: G
authors.lastname: Tigyi
authors.forename: Duane D
authors.initials: DD
authors.lastname: Miller
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy; D008546:Melanoma, Experimental / Q000188:drug therapy; D051379:Mice; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009281:Naphthalenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D063065:Organophosphonates / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D009943:Organophosphorus Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D043264:Phosphodiesterase I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000099189:Lysophospholipase D
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D009281:Naphthalenes; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D043264:Phosphodiesterase I; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases; D000099189:Lysophospholipase D; C560360:4-pentadecylbenzylphosphonic acid; C031721:naphthalene; C032627:methylphosphonic acid; C475503:benzylphosphonic acid