Banerjee Souvik, Norman Derek D, Lee Sue Chin, Parrill Abby L, Pham Truc Chi T, Baker Daniel L, Tigyi Gabor J, Miller Duane D
Department of Pharmaceutical Sciences, College of Pharmacy, ‡Department of Physiology, College of Medicine, University of Tennessee Health Science Center , Memphis, Tennessee 38163, United States.
Department of Chemistry, ∥Computational Research on Materials Institute, The University of Memphis , Memphis, Tennessee 38152, United States.
J Med Chem. 2017 Feb 23;60(4):1309-1324. doi: 10.1021/acs.jmedchem.6b01270. Epub 2017 Feb 10.
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.
自分泌运动因子（ATX，又名ENPP2）是生物体液中脂质介质溶血磷脂酸（LPA）的主要来源。本研究报道了通过对苯磺酰胺类计算机虚拟筛选命中化合物3进行先导优化而得到的ATX抑制剂。这些新类似物提供了苯磺酰胺支架的全面构效关系，从而产生了一系列高效的ATX抑制剂。三种最有效的类似物（3a，IC约为32 nM；3b，IC约为9 nM；以及14，IC约为35 nM）在体外抑制A2058人黑色素瘤细胞的ATX依赖性侵袭。两种最有效的化合物3b和3f（IC约为84 nM）对ENPP6和ENPP7没有抑制作用，但对LPA G蛋白偶联受体具有微弱的拮抗作用。特别是，化合物3b有效降低了4T1乳腺癌干细胞样细胞对紫杉醇的体外化疗耐药性，并显著降低了体内B16黑色素瘤转移。
