3HDN

Crystal structure of serum and glucocorticoid-regulated kinase 1 in complex with compound 2

Summary for 3HDN

• Entry DOI: 10.2210/pdb3hdn/pdb
• Related: 3HDM
• Descriptor: Serine/threonine-protein kinase Sgk1, [4-(5-naphthalen-2-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl]acetic acid (3 entities in total)
• Functional Keywords: agc protein kinase, apoptosis, atp-binding, endoplasmic reticulum, nucleotide-binding, nucleus, phosphorylation, serine/threonine-protein kinase, transferase, kinase, phosphoprotein
• Biological source: Homo sapiens (human)
• Cellular location: Isoform 2: Cell membrane. Cytoplasm: O00141
• Total number of polymer chains: 1
• Total formula weight: 42681.74

Authors

Zhao, B.,Hammond, M. (deposition date: 2009-05-07, release date: 2009-06-30, Last modification date: 2024-02-21)

Primary citation

Hammond, M.,Washburn, D.G.,Hoang, H.T.,Manns, S.,Frazee, J.S.,Nakamura, H.,Patterson, J.R.,Trizna, W.,Wu, C.,Azzarano, L.M.,Nagilla, R.,Nord, M.,Trejo, R.,Head, M.S.,Zhao, B.,Smallwood, A.M.,Hightower, K.,Laping, N.J.,Schnackenberg, C.G.,Thompson, S.K.
Design and synthesis of orally bioavailable serum and glucocorticoid-regulated kinase 1 (SGK1) inhibitors.
Bioorg.Med.Chem.Lett., 19:4441-4445, 2009

PubMed Abstract: The lead serum and glucocorticoid-related kinase 1 (SGK1) inhibitors 4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzoic acid (1) and {4-[5-(2-naphthalenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]phenyl}acetic acid (2) suffer from low DNAUC values in rat, due in part to formation and excretion of glucuronic acid conjugates. These PK/glucuronidation issues were addressed either by incorporating a substituent on the 3-phenyl ring ortho to the key carboxylate functionality of 1 or by substituting on the group in between the carboxylate and phenyl ring of 2. Three of these analogs have been identified as having good SGK1 inhibition potency and have DNAUC values suitable for in vivo testing.

PubMed: 19497745
DOI: 10.1016/j.bmcl.2009.05.051

Experimental method

X-RAY DIFFRACTION (3.1 Å)