Aromatic phosphonates inhibit the lysophospholipase D activity of autotaxin
Guowei Jiang1, Damian Madan, Glenn D Prestwich
1Department of Medicinal Chemistry, The University of Utah, 419 Wakara Way, Suite 205, Salt Lake City, UT 84108-1257, USA.
Abstract:
Autotaxin (ATX) is an attractive target for the anticancer therapeutics that inhibits angiogenesis, invasion and migration. ATX is an extracellular lysophospholipase D that hydrolyzes lysophosphatidylcholine to form the bioactive lipid lysophosphatidic acid. The aromatic phosphonate S32826 was the first described nanomolar inhibitor of ATX. However, the tridecylamide substituent on aromatic ring contributed to its poor solubility and bioavailability, severely limiting its utility in vivo. cLogP calculations revealed that the lipophilicity of S32826 could be lowered by shortening its hydrophobic chain and by introducing substituents alpha to the phosphonate. Herein, we describe the synthesis of a small set of α-substituted phosphonate analogs of S32826, and we show that shortening the chain and adding α-halo or α-hydroxy substituents increased solubility; however, ATX inhibition was reduced by most substitutions. An optimal compound was identified for examination of biological effects of ATX inhibition in vivo.
Insights
Researchers modified an autotaxin (ATX) inhibitor, S32826, to improve solubility for cancer therapy. While modifications enhanced solubility, they reduced ATX inhibition, leading to an optimized compound for further in vivo studies.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Pharmacology
Background:
- Autotaxin (ATX) is a key target for anticancer therapeutics due to its roles in angiogenesis, invasion, and migration.
- ATX hydrolyzes lysophosphatidylcholine to form lysophosphatidic acid, a bioactive lipid.
- The previously developed ATX inhibitor, S32826, exhibited nanomolar potency but suffered from poor solubility and bioavailability.
Purpose of the Study:
- To synthesize and evaluate novel α-substituted phosphonate analogs of S32826.
- To improve the solubility and bioavailability of ATX inhibitors.
- To identify an optimized compound for in vivo evaluation of ATX inhibition's biological effects.
Main Methods:
- Synthesis of α-substituted phosphonate analogs of S32826.
- Evaluation of compound solubility and lipophilicity (cLogP).
- Assessment of ATX inhibitory activity in vitro.
Main Results:
- Shortening the hydrophobic chain and introducing α-halo or α-hydroxy substituents increased compound solubility.
- Most α-substituted analogs showed reduced ATX inhibitory activity compared to S32826.
- An optimal compound with improved solubility was identified for further biological examination.
Conclusions:
- Modifications to S32826 can enhance solubility but may compromise ATX inhibitory potency.
- Further optimization is required to balance solubility and efficacy for developing effective ATX-targeted anticancer drugs.
- The identified optimal compound warrants in vivo investigation for its therapeutic potential.
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