GRI918013

GRI918013 (compound 1) is a selective and competitive autotaxin (ATX/NPP2) inhibitor with anti-invasiv e and anti-metastatic activity. GRI918013 competitively binds to ATX, blocking lipid substrates such as lysophosphatidylcholine (LPC) from entering the ATX active site, thereby inhibiting ATX-mediated hydrolysis of LPC to lysophosphatidic acid (LPA), and consequently inhibiting ATX-LPA axis -related tumor cell invasion and metastasis. GRI918013 inhibits ATX-mediated hydrolysis of the LPL substrate FS-3 ( IC₅₀ = 31.42 nM, K i =12.98 nM). GRI918013 can be used in research on cancer invasion and metastasis, such as melanoma, and can also serve as a tool compound for ATX-LPA axis-related diseases such as fibrotic diseases, neuropathic pain, and cholestatic pruritus ^[1].

In Vivo, GRI918013 (30 µg/mouse; i.p.; daily; 10 days) reduces lung metastasis in female C57BL/6 mice with B16-F10 melanoma^[1].

In Vitro, GRI918013 (10 µM; 3 h) competitively inhibits ATX-mediated FS-3 hydrolysis (IC₅₀=31.42 nM; Ki=12.98 nM), but does not inhibit the hydrolysis of the phosphodiesterase (PDE) substrate pNP-TMP, and has no effect on NPP6, NPP7, or LPA and S1P receptors^[1]. GRI918013 (10 µM; 2 h) inhibits the hydrolysis of four substrates, LPC 14:0, LPC 16:0, LPC 18:0, and LPC 18:1, mediated by ATX, with inhibition rates of 41.0%, 55.4%, 43.6%, and 51.8%, respectively^[1]. GRI918013 dose-dependently inhibits ATX-dependent A2058 cell invasion (IC₅₀ = 118.79 nM, 16 h)^[1]. GRI918013 has reduced inhibitory potency on ATXF275A mutant (IC₅₀ >10 μM vs ATXWT 3.0 μM) and maintains potency on ATXY83A mutant (IC₅₀=0.15 μM)^[1]. GRI918013 (10 µM; 4 h) inhibits ATX-mediated ADMAN-LPC hydrolysis by 89.0%^[1].

References:
[1]. Fells JI, et al. Hits of a high-throughput screen identify the hydrophobic pocket of autotaxin/lysophospholipase D as an inhibitory surface. Mol Pharmacol. 2013;84(3):415-424.