ONO-8430506: A Novel Autotaxin Inhibitor That Enhances the Antitumor Effect of Paclitaxel in a Breast Cancer Model

Iwaki, Yuzo; Ohhata, Akira; Nakatani, Shingo; Hisaichi, Katsuya; Okabe, Yasuyuki; Hiramatsu, Atsushi; Watanabe, Toshihide; Yamamoto, Shingo; Nishiyama, Taihei; Kobayashi, Juta; Hirooka, Yasuo; Moriguchi, Hideki; Maeda, Takeyasu; Katoh, Makoto; Komichi, Yuka; Ota, Hiroto; Matsumura, Naoya; Okada, Masahiro; Sugiyama, Tetsuya; Saga, Hiroshi; Imagawa, Akira

doi:10.1021/acsmedchemlett.0c00200

Cited by 21 publications

(23 citation statements)

References 20 publications

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“…The ATX inhibitor ONO-8430506 efficiently inhibited the ATX activity and decreased LPA levels in the plasma when orally administered in rodents 32 – 35 . However, its effects on the ATX and LPA levels in CSF have not been tested.…”

Section: Resultsmentioning

confidence: 99%

“…There are several lines of data showing the possible usefulness of the ATX inhibitory agents for the treatment of various diseases caused by LPA, including breast and thyroid cancer, and urethral tension 32 – 35 , 58 , 59 . With sufficient inhibition of the ATX activity, these treatments generally do not affect the general conditions of the experimental animals.…”

Section: Discussionmentioning

confidence: 99%

“…Accordingly, we examined for the first time the effect of an ATX inhibitor on the progression of NP using a NP model with compression of DRG (CD model) in rats, which is considered as one of the models of lumbar spinal canal stenosis (LSS) 29 and as a proxy for radicular pain in patients with LSS 30 , 31 . As an ATX inhibitor, we used a recently developed one, which has optimized enzymatic activity by carboxyl group incorporation and gained the novel, most potent and orally available compound ONO-8430506, among others 32 .…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of autotaxin activity ameliorates neuropathic pain derived from lumbar spinal canal stenosis

Uranbileg

Ito

Kurano

et al. 2021

Sci Rep

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Lumbar spinal canal stenosis (LSS) or mechanical compression of dorsal root ganglion (DRG) is one of the causes of low back pain and neuropathic pain (NP). Lysophosphatidic acid (LPA) is a potent bioactive lipid mediator that is produced mainly from lysophosphatidylcholine (LPC) via autotaxin (ATX) and is known to induce NP via LPA1 receptor signaling in mice. Recently, we demonstrated that LPC and LPA were higher in cerebrospinal fluid (CSF) of patients with LSS. Based on the possible potential efficacy of the ATX inhibitor for NP treatment, we used an NP model with compression of DRG (CD model) and investigated LPA dynamics and whether ATX inhibition could ameliorate NP symptoms, using an orally available ATX inhibitor (ONO-8430506) at a dose of 30 mg/kg. In CD model, we observed increased LPC and LPA levels in CSF, and decreased threshold of the pain which were ameliorated by oral administration of the ATX inhibitor with decreased microglia and astrocyte populations at the site of the spinal dorsal horn projecting from injured DRG. These results suggested possible efficacy of ATX inhibitor for the treatment of NP caused by spinal nerve root compression and involvement of the ATX-LPA axis in the mechanism of NP induction.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Inhibition of autotaxin activity ameliorates neuropathic pain derived from lumbar spinal canal stenosis

Uranbileg

Ito

Kurano

et al. 2021

Sci Rep

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“…The compound was able to decrease intraurethral pressure similarly to clinically used tamsulosin, an α1-adrenoceptor antagonist, without changing mean blood pressure. 244 This inhibitor was also proven to have antitumor effects in preclinical metastatic breast and thyroid cancer models, 188 , 245 , 246 showing the versatile potential of ATX inhibitors for the treatment of human diseases.…”

Section: Lpa Signaling As a Therapeutic Targetmentioning

confidence: 99%

Role of lysophosphatidic acid and its receptors in health and disease: novel therapeutic strategies

Geraldo

Spohr

Amaral

et al. 2021

Sig Transduct Target Ther

176

150

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Lysophosphatidic acid (LPA) is an abundant bioactive phospholipid, with multiple functions both in development and in pathological conditions. Here, we review the literature about the differential signaling of LPA through its specific receptors, which makes this lipid a versatile signaling molecule. This differential signaling is important for understanding how this molecule can have such diverse effects during central nervous system development and angiogenesis; and also, how it can act as a powerful mediator of pathological conditions, such as neuropathic pain, neurodegenerative diseases, and cancer progression. Ultimately, we review the preclinical and clinical uses of Autotaxin, LPA, and its receptors as therapeutic targets, approaching the most recent data of promising molecules modulating both LPA production and signaling. This review aims to summarize the most update knowledge about the mechanisms of LPA production and signaling in order to understand its biological functions in the central nervous system both in health and disease.

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“…All these derivatives were found to be among the most powerful ATX inhibitors (both in vitro and ex vivo in human whole blood) reported to date in the literature. Recently, ONO Pharmaceutical introduced the tetrahydrocarboline-based inhibitor ONO-8430506, with IC 50 values of 5.1 nM and 4.5 nM in the FS-3 and LPC assay, respectively [ 52 , 53 ]. Other ATX inhibitors that have been developed include the pipemidic acid-based molecule H2L-7905958 ( Figure 1 ) [ 54 , 55 ], various antioxidants, such as polyphenols and phenolic acids [ 56 ], benzene-sulfonamide-based derivatives (I, Figure 1 ) [ 31 , 57 ], indole-thioether carboxylic acid derivatives (II, Figure 1 ) (Inc. 2012), pyridazines (III, Figure 1 ) and tetrahydropyridopyrimidine derivatives [ 58 , 59 ], as well as benzoxazolone or benzotriazole- [ 60 ], imidazole- [ 61 ] and benzonaphthyridinamine-based analogues [ 62 , 63 ].…”

Section: Introductionmentioning

confidence: 99%

Structure-Based Discovery of Novel Chemical Classes of Autotaxin Inhibitors

Magkrioti

Kaffe

Stylianaki

et al. 2020

IJMS

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Autotaxin (ATX) is a secreted glycoprotein, widely present in biological fluids, largely responsible for extracellular lysophosphatidic acid (LPA) production. LPA is a bioactive growth-factor-like lysophospholipid that exerts pleiotropic effects in almost all cell types, exerted through at least six G-protein-coupled receptors (LPAR1-6). Increased ATX expression has been detected in different chronic inflammatory diseases, while genetic or pharmacological studies have established ATX as a promising therapeutic target, exemplified by the ongoing phase III clinical trial for idiopathic pulmonary fibrosis. In this report, we employed an in silico drug discovery workflow, aiming at the identification of structurally novel series of ATX inhibitors that would be amenable to further optimization. Towards this end, a virtual screening protocol was applied involving the search into molecular databases for new small molecules potentially binding to ATX. The crystal structure of ATX in complex with a known inhibitor (HA-155) was used as a molecular model docking reference, yielding a priority list of 30 small molecule ATX inhibitors, validated by a well-established enzymatic assay of ATX activity. The two most potent, novel and structurally different compounds were further structurally optimized by deploying further in silico tools, resulting to the overall identification of six new ATX inhibitors that belong to distinct chemical classes than existing inhibitors, expanding the arsenal of chemical scaffolds and allowing further rational design.

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ONO-8430506: A Novel Autotaxin Inhibitor That Enhances the Antitumor Effect of Paclitaxel in a Breast Cancer Model

Cited by 21 publications

References 20 publications

Inhibition of autotaxin activity ameliorates neuropathic pain derived from lumbar spinal canal stenosis

Inhibition of autotaxin activity ameliorates neuropathic pain derived from lumbar spinal canal stenosis

Role of lysophosphatidic acid and its receptors in health and disease: novel therapeutic strategies

Structure-Based Discovery of Novel Chemical Classes of Autotaxin Inhibitors

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