Designing Dual Inhibitors of Autotaxin-LPAR GPCR Axis

Abstract

The ATX-LPA-LPAR1 signaling pathway plays a universal role in stimulating diverse cellular responses, including cell proliferation, migration, survival, and invasion in almost every cell type. The ATX-LPAR1 axis is linked to several metabolic and inflammatory diseases including cancer, fibrosis, and rheumatoid arthritis. Numerous selective ATX or LPAR1 inhibitors have been developed and so far, their clinical efficacy has only been evaluated in idiopathic pulmonary fibrosis. None of the ATX and LPAR1 inhibitors have advanced to clinical trials for cancer and rheumatoid arthritis. Nonetheless, several research groups, including ours, have shown considerable benefit of simultaneous ATX and LPAR1 inhibition through combination therapy. Recent research suggests that dual-targeting therapies are superior to combination therapies that use two selective inhibitors. However, limited reports are available on ATX-LPAR1 dual inhibitors, potentially due to co-expression of multiple different LPARs with close structural similarities at the same target. In this review, we discuss rational design and future directions of dual ATX-LPAR1 inhibitors.

Decreased Lipid Phosphate Phosphatase 1/3 and Increased Lipid Phosphate Phosphatase 2 Expression in the Human Breast Cancer Tumor Microenvironment Promotes Tumor Progression and Immune System Evasion

“…Pre-clinical investigations in both cell cultures and murine tumor models have provided considerable support for inhibitors against the ATX-LPAR-LPP pathway, some of which, especially against ATX and the LPARs, are currently in clinical trials [ 4 , 27 , 28 , 29 , 30 , 31 ]. However, there are no therapies under clinical investigation to restore LPP1/3 levels or suppress LPP2 levels in cancers.…”

Autotaxin inhibitor IOA-289 reduces gastrointestinal cancer progression in preclinical models

“…In the last years, several small molecules have been developed to act as ATX inhibitors. These molecules can act by competing with LPC for the hydrophobic pocket and by binding to the active site of the enzyme [ 15 ]. IOA-289 is an orally available ATX inhibitor in clinical development by iOnctura for the treatment of solid tumors with a high degree of fibrosis [ 16 ].…”

Autotaxin and Lysophosphatidate Signaling: Prime Targets for Mitigating Therapy Resistance in Breast Cancer

“…Class I are lipid-like or orthosteric inhibitors, with the early inhibitor PF-8380 being the prototypical inhibitor of this class [ 84 , 85 ]. None of these compounds have entered advanced clinical trials, secondary to their off-target effects related to their high partition coefficient [ 86 ]. More modern inhibitors are non-carboxylic and non-lipid in design [ 86 ].…”

“…None of these compounds have entered advanced clinical trials, secondary to their off-target effects related to their high partition coefficient [ 86 ]. More modern inhibitors are non-carboxylic and non-lipid in design [ 86 ]. Class II inhibitors target the hydrophobic pocket (including GRI-918013, none of which are in trials), obstructing binding of LPC to ATX [ 83 ].…”

“…Such inhibitors, however, may not have the intended therapeutic potency if the other LPARs can adequately compensate following their blockage, but further investigation in animal models will be required to determine this. If this were to be the case, a combination compound in the form of a dual ATX-inhibitor and selective LPAR inhibitor might be able to provide robust adjuvant therapy, as has been demonstrated with dual ATX-LPAR1 inhibition in metastatic melanoma models [ 86 , 106 ]. Finally, pharmacological targeting of the LPPs remains an essentially untapped area of investigation.…”