6MO4

Co-Crystal structure of P. aeruginosa LpxC-50067 complex

Summary for 6MO4

• Entry DOI: 10.2210/pdb6mo4/pdb
• Descriptor: UDP-3-O-acyl-N-acetylglucosamine deacetylase, MAGNESIUM ION, N-[(2R)-1-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-1-oxobutan-2-yl]-4-(6-hydroxyhexa-1,3-diyn-1-yl)benzamide, ... (4 entities in total)
• Functional Keywords: hydrolase lpxc pseudomonas aeruginosa, hydrolase, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Pseudomonas aeruginosa PAO1
• Total number of polymer chains: 1
• Total formula weight: 34048.86

Authors

Stein, A.J.,Assar, Z.,Holt, M.C.,Cohen, F.,Andrews, L.,Cirz, R. (deposition date: 2018-10-04, release date: 2019-07-17, Last modification date: 2024-03-13)

Primary citation

Cohen, F.,Aggen, J.B.,Andrews, L.D.,Assar, Z.,Boggs, J.,Choi, T.,Dozzo, P.,Easterday, A.N.,Haglund, C.M.,Hildebrandt, D.J.,Holt, M.C.,Joly, K.,Jubb, A.,Kamal, Z.,Kane, T.R.,Konradi, A.W.,Krause, K.M.,Linsell, M.S.,Machajewski, T.D.,Miroshnikova, O.,Moser, H.E.,Nieto, V.,Phan, T.,Plato, C.,Serio, A.W.,Seroogy, J.,Shakhmin, A.,Stein, A.J.,Sun, A.D.,Sviridov, S.,Wang, Z.,Wlasichuk, K.,Yang, W.,Zhou, X.,Zhu, H.,Cirz, R.T.
Optimization of LpxC Inhibitors for Antibacterial Activity and Cardiovascular Safety.
Chemmedchem, 14:1560-1572, 2019

PubMed Abstract: UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) is a Zn deacetylase that is essential for the survival of most pathogenic Gram-negative bacteria. ACHN-975 (N-((S)-3-amino-1-(hydroxyamino)-3-methyl-1-oxobutan-2-yl)-4-(((1R,2R)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)benzamide) was the first LpxC inhibitor to reach human clinical testing and was discovered to have a dose-limiting cardiovascular toxicity of transient hypotension without compensatory tachycardia. Herein we report the effort beyond ACHN-975 to discover LpxC inhibitors optimized for enzyme potency, antibacterial activity, pharmacokinetics, and cardiovascular safety. Based on its overall profile, compound 26 (LPXC-516, (S)-N-(2-(hydroxyamino)-1-(3-methoxy-1,1-dioxidothietan-3-yl)-2-oxoethyl)-4-(6-hydroxyhexa-1,3-diyn-1-yl)benzamide) was chosen for further development. A phosphate prodrug of 26 was developed that provided a solubility of >30 mg mL for parenteral administration and conversion into the active drug with a t of approximately two minutes. Unexpectedly, and despite our optimization efforts, the prodrug of 26 still possesses a therapeutic window insufficient to support further clinical development.

PubMed: 31283109
DOI: 10.1002/cmdc.201900287

Experimental method

X-RAY DIFFRACTION (1.844 Å)