Novel Autotaxin Inhibitor ATX-1d Significantly Enhances Potency of Paclitaxel-An In Silico and In Vitro Study

The development of drug resistance in cancer cells poses a significant challenge for treatment, with nearly 90% of cancer-related deaths attributed to it. Over 50% of ovarian cancer patients and 30-40% of breast cancer patients exhibit resistance to therapies such as Taxol. Previous literature has shown that cytotoxic cancer therapies and ionizing radiation damage tumors, prompting cancer cells to exploit the autotaxin (ATX)-lysophosphatidic acid (LPA)-lysophosphatidic acid receptor (LPAR) signaling axis to enhance survival pathways, thus reducing treatment efficacy. Therefore, targeting this signaling axis has become a crucial strategy to overcome some forms of cancer resistance. Addressing this challenge, we identified and assessed ATX-1d, a novel compound targeting ATX, through computational methods and in vitro assays. ATX-1d exhibited an IC₅₀ of 1.8 ± 0.3 μM for ATX inhibition and demonstrated a significant binding affinity for ATX, as confirmed by MM-GBSA, QM/MM-GBSA, and SAPT in silico methods. ATX-1d significantly amplified the potency of paclitaxel, increasing its effectiveness tenfold in 4T1 murine breast carcinoma cells and fourfold in A375 human melanoma cells without inducing cytotoxic effects as a single agent.