Highly Potent Non-Carboxylic Acid Autotaxin Inhibitors Reduce Melanoma Metastasis and Chemotherapeutic Resistance of Breast Cancer Stem Cells

Abstract

Autotaxin (ATX, aka. ENPP2) is the main source of the lipid mediator lysophosphatidic acid (LPA) in biological fluids. This study reports on inhibitors of ATX derived by lead optimization of the benzene-sulfonamide in silico hit compound 3. The new analogues provide a comprehensive structure-activity relationship of the benzene-sulfonamide scaffold that yielded a series of highly potent ATX inhibitors. The three most potent analogues (3a, IC ∼ 32 nM; 3b, IC ∼ 9 nM; and 14, IC ∼ 35 nM) inhibit ATX-dependent invasion of A2058 human melanoma cells in vitro. Two of the most potent compounds, 3b and 3f (IC ∼ 84 nM), lack inhibitory action on ENPP6 and ENPP7 but possess weak antagonist action specific to the LPA G protein-coupled receptor. In particular, compound 3b potently reduced in vitro chemotherapeutic resistance of 4T1 breast cancer stem-like cells to paclitaxel and significantly reduced B16 melanoma metastasis in vivo.

Role of autotaxin in cancer stem cells

“…Moreover, ovarian CSC produced high levels of LPA via an ATX-dependent mechanism, and knockdown or pharmacological inhibition of ATX markedly attenuated the LPA-producing, tumorigenic, and drug resistance potentials of ovarian CSC. Consistently, ATX inhibitors reduced melanoma metastasis and chemoresistance of breast CSC [69]. These results suggest that ATX-LPA signaling axis plays a pivotal role in the tumorigenic, drug-resistance, and metastatic potentials of CSC.…”

“…Pharmacological inhibition or knockdown of periostin can block proliferation of drug-resistant cells by reducing the expression of CSC-associated genes, including OCT4, SOX2, ALDH1A1 , and those encoding ABC transporters. Moreover, compound 3b, an ATX inhibitor derived by lead optimization of the benzene-sulfonamide in silico hit compound 3, was reported to potently reduce the drug resistance of breast CSC [69]. These results suggest the potential of ATX inhibitors in cancer therapy by targeting therapy-resistant CSC.…”

Morpholine as a privileged structure: A review on the medicinal chemistry and pharmacological activity of morpholine containing bioactive molecules

“…Based on a recent high‐throughput and in silico screening study compound 52 (Figure ) was identified as a potent autotaxin inhibitor with an IC 50 of 117 nM . Optimization of compound 52 led to a long series of morpholine‐containing inhibitors with the most potent inhibitor of this series, compound 53 (Figure ), bearing an IC 50 of 9 nM . Among other SAR investigations, replacement of the morpholine moiety in the most potent derivatives with piperazine led to a considerable loss of potency.…”

“…Compound 53 inhibited ATX‐dependent human melanoma cell invasion in vitro as well as reduced B16 melanoma metastasis in vivo (mice). It was also able to reduce the resistance of breast cancer‐like cells to paclitaxel treatment, serving as a possible adjunct for chemotherapeutic resistant cancers …”

Association between serum autotaxin or phosphatidylserine‐specific phospholipase A1 levels and melanoma

“…Regarding melanoma, LysoPA has been demonstrated to be involved in the tumorigenesis of melanoma, as well as other kinds of cancers, based on a series of elegant basic studies; LPA 1 and LPA 5 are reported to be involved in the invasion and metastasis of melanoma, while LPA 3 is reportedly involved in the growth and survival of metastatic melanoma . In addition, several studies have demonstrated that the pharmacological inhibition of ATX or LysoPA activities may possibly block the migration of melanoma . Therefore, ATX is expected to be a candidate target for the treatment of melanoma, for which the prognosis is generally poor.…”