5L0K

Crystal Structure of Autotaxin and Compound PF-8380

Summary for 5L0K

• Entry DOI: 10.2210/pdb5l0k/pdb
• Related: 5L0B 5L0E
• Descriptor: Ectonucleotide pyrophosphatase/phosphodiesterase family member 2, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (9 entities in total)
• Functional Keywords: phospholipase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Rattus norvegicus (Rat)
• Total number of polymer chains: 2
• Total formula weight: 188869.98

Authors

Durbin, J.D. (deposition date: 2016-07-27, release date: 2016-08-10, Last modification date: 2024-11-13)

Primary citation

Jones, S.B.,Pfeifer, L.A.,Bleisch, T.J.,Beauchamp, T.J.,Durbin, J.D.,Klimkowski, V.J.,Hughes, N.E.,Rito, C.J.,Dao, Y.,Gruber, J.M.,Bui, H.,Chambers, M.G.,Chandrasekhar, S.,Lin, C.,McCann, D.J.,Mudra, D.R.,Oskins, J.L.,Swearingen, C.A.,Thirunavukkarasu, K.,Norman, B.H.
Novel Autotaxin Inhibitors for the Treatment of Osteoarthritis Pain: Lead Optimization via Structure-Based Drug Design.
Acs Med.Chem.Lett., 7:857-861, 2016

PubMed Abstract: In an effort to develop a novel therapeutic agent aimed at addressing the unmet need of patients with osteoarthritis pain, we set out to develop an inhibitor for autotaxin with excellent potency and physical properties to allow for the clinical investigation of autotaxin-induced nociceptive and neuropathic pain. An initial hit identification campaign led to an aminopyrimidine series with an autotaxin IC50 of 500 nM. X-ray crystallography enabled the optimization to a lead compound that demonstrated favorable potency (IC50 = 2 nM), PK properties, and a robust PK/PD relationship.

PubMed: 27660691
DOI: 10.1021/acsmedchemlett.6b00207

Experimental method

X-RAY DIFFRACTION (2.73 Å)