A Novel Autotaxin Inhibitor Reduces Lysophosphatidic Acid Levels in Plasma and the Site of Inflammation

Lysophosphatidic acid receptors (LPARs): Potential targets for the treatment of neuropathic pain

“…In this regard, the humanized monoclonal antibody, anti-LPA B3, that targets LPA, is currently under investigation (Crack et al, 2014;Goldshmit et al, 2012). An alternative approach may be to target the enzyme ATX (Gierse et al, 2010;Gupte et al, 2011;Hwang et al, 2013), which contributes to LPA production. There are currently several ATX inhibitors in pre-clinical studies, although none are exclusive for NP.…”

“…There are currently several ATX inhibitors in pre-clinical studies, although none are exclusive for NP. PF-8380 is a specific inhibitor that reduces inflammatory hyperalgesia in rats within 3h (Gierse et al, 2010). Other ATX inhibitors, such as 4PBPA (Gupte et al, 2011), Gintonin (Hwang et al, 2013) and ONO-8430506 (Benesch et al, 2014) are indicated for cancer, although they may also have effects on NP (see Table 1).…”

Recent advances in targeting the autotaxin-lysophosphatidate-lipid phosphate phosphatase axis in vivo

“…Because LPA is rapidly turned over, plasma LPA levels fall by >95﹪ upon treatment with a potent ATX inhibitor [140] . There are numerous small non-lipid molecules that have been discovered and modified to inhibit ATX activity through screening large libraries of compounds [141][142] .…”

“…It was the first reported ATX inhibitor to reduce plasma LPA levels in vivo for an extended period [140] . In rat air-pouch models, 30 mg/kg PF-8380 inhibited inflammatory hyperalgesia with the same efficacy as 30 mg/kg naproxen, a routinely used nonsteroidal anti-inflammatory drug Inflammatory hyperalgesia [140] Radiotherapy sensitizer in glioblastoma [146] ONO-8430506 Autotaxin activity inhibitor (competitive) Preclinical IC 50 5 nmol/L 10-30 mg/kg Benign prostatic hyperplasia [147] Reduces breast tumor growth and metastasis and increases sensitization to doxorubicin [76,148] Lpathomab TM LPA monoclonal antibody Preclinical 25 mg/kg Traumatic brain injury [127] AM966 LPA 1 antagonist Preclinical IC 50 17 nmol/L 10 mg/kg Idiopathic pulmonary fibrosis [132] BMS-986020 LPA 1 antagonist Phase II 600 mg/day (patients) Idiopathic pulmonary fibrosis [133] BMS-986202/AM152 LPA 1 antagonist Phase I 20-40 mg/kg Idiopathic pulmonary fibrosis [134] SAR100842 LPA 1/3 antagonist Phase II 20-40 mg/kg Systemic sclerosis [135] Gene overexpression Induced LPP gene expression Preclinical Overexpressed in cancer cells LPP3 overexpression reduces ovarian cancer cell growth [118] LPP1 overexpression reduces tumor growth and metastasis in breast and thyroid cancers [116] (NSAID) [140] . At this concentration, PF-8380 maximally reduced LPA levels in both plasma and at the site of inflammation.…”

Dendrimer Conjugate of [4-(Tetradecanoylamino)benzyl]phosphonic Acid (S32826) as an Autotaxin Inhibitor

“…18 More recently there have been a number of nonlipid autotaxin inhibitors identified, of which two, HA150 and PF8380, have been shown to lower LPA levels in vivo. 19,20 However, the effect of these compounds on LPA receptors has not yet been fully investigated. Thus, there remains a need to identify specific autotaxin inhibitors with appropriate druglike properties.…”