Discovery and optimization of ATX inhibitors via modeling, synthesis and biological evaluation

Pharmacophoric Site Identification and Inhibitor Design for Autotaxin

“…This domain consists of a catalytic site for hydrolytic activity with conserved zinc ions, a hydrophobic pocket, a hydrophobic tunnel and a T-shaped structure [11,12,48,49]. Previously, we designed ATX inhibitors targeting the catalytic site and the hydrophobic pocket [43,44]. These compounds exhibited a binding mode similar to the known ATX inhibitors such as 3BoA from the University of Tokyo [50] and PF-8380 from Pfizer Inc. [45].…”

“…Most importantly, we developed a selective interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor using this approach [41]. Our research group has also reported potent ATX inhibitors in our previous papers [43,44]. In the present study, we carried out molecular dynamics (MD) simulation on the ATX structure in the apo state.…”

Development and therapeutic potential of autotaxin small molecule inhibitors: From bench to advanced clinical trials

“…Additionally, a favorable structural and charge correspondence was established between the phosphonic acid group of 61 and the methanesulfonamide group of 65 , both participating in electrostatic interactions with the catalytic zinc ions . Further optimization on this series was orientated toward decreasing the number of the aromatic rings of 61 and 65 (compounds 66 and 67 ; Figure ) in conjunction with replacing the polar and acidic head groups with other isosteres (compounds 68 and 69 ; Figure ), an exercise that ultimately afforded the very potent ATX inhibitors 66 (IC 50 = 1.23 nM) and 69 (IC 50 = 4.62 nM) . Docking studies showed that 66 binds to ATX in a similar to its progenitor 61 fashion, with the phenyl and piperidine rings of the linker further involved in π‐anion and hydrophobic interactions with Asp 171 and Tyr 306 , respectively.…”

“…Compound 66 is also a potent ATX inhibitor ex vivo (human plasma assay, IC 50 = 136 nM), exhibiting at the same time a powerful anticancer effect in both liver cancer and melanoma cell lines (EC 50 = 7.90 and 1.30 nM, respectively). Likewise, 66 displayed a very promising pharmacokinetic profile after a single intravenous administration in rats, being also metabolically stable in human and rat liver microsomes . Nonetheless, the very polar and highly charged properties of the phosphonic acid group renders 66 unsuitable for oral administration.…”

“…Further exploration of structure activity relationship studies in PF8380‐based inhibitors and development of allosteric autotaxin inhibitors (mode of binding of this series is also depicted) [Color figure can be viewed at wileyonlinelibrary.com]…”