CHIR-090 | CAS#728865-23-4 | LpxC inhibitor

MedKoo Cat#: 526733 | Name: CHIR-090

Description:

WARNING: This product is for research use only, not for human or veterinary use.

CHIR-090 is a very potent and selective LpxC inhibitor. CHIR-090 has excellent antibiotic activity against Pseudomonas aeruginosa and Escherichia coli. CHIR-090 is also a two-step slow, tight-binding inhibitor of E. coli LpxC with Ki = 4.0 nM, Ki* = 0.5 nM, k5 = 1.9 min-1, and k6 = 0.18 min-1. CHIR-090 at low nanomolar levels inhibits LpxC orthologues from diverse Gram-negative pathogens, including P. aeruginosa, Neisseria meningitidis, and Helicobacter pylori. In contrast, CHIR-090 is a relatively weak competitive and conventional inhibitor (lacking slow, tight-binding kinetics) of LpxC from Rhizobium leguminosarum (Ki = 340 nM), a Gram-negative plant endosymbiont that is resistant to this compound. CHIR-090 is an excellent lead for the further development of new antibiotics targeting the lipid A pathway.

Chemical Structure

CHIR-090

CAS#728865-23-4

Theoretical Analysis

MedKoo Cat#: 526733

Name: CHIR-090

CAS#: 728865-23-4

Chemical Formula: C24H27N3O5

Exact Mass: 437.1951

Molecular Weight: 437.50

Elemental Analysis: C, 65.89; H, 6.22; N, 9.60; O, 18.28

Price and Availability

Size	Price	Availability
5mg	USD 90.00	Same day
10mg	USD 150.00	Same day
25mg	USD 250.00	Same day
50mg	USD 450.00	Same day
100mg	USD 750.00	Same day
200mg	USD 1,350.00	Same day

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Synonym

CHIR-090; CHIR 090; CHIR090.

IUPAC/Chemical Name

N-[(2S,3R)-3-hydroxy-1-(hydroxyamino)-1-oxobutan-2-yl]-4-[2-[4-(morpholin-4-ylmethyl)phenyl]ethynyl]benzamide

InChi Key

FQYBTYFKOHPWQT-VGSWGCGISA-N

InChi Code

InChI=1S/C24H27N3O5/c1-17(28)22(24(30)26-31)25-23(29)21-10-8-19(9-11-21)3-2-18-4-6-20(7-5-18)16-27-12-14-32-15-13-27/h4-11,17,22,28,31H,12-16H2,1H3,(H,25,29)(H,26,30)/t17-,22+/m1/s1

SMILES Code

O=C(N[C@@H]([C@H](O)C)C(NO)=O)C1=CC=C(C#CC2=CC=C(CN3CCOCC3)C=C2)C=C1

Appearance

White to off-white solid powder

Purity

>98% (or refer to the Certificate of Analysis)

Shipping Condition

Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition

Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility

Soluble in DMSO, not in water

Shelf Life

>2 years if stored properly

Drug Formulation

This drug may be formulated in DMSO

Stock Solution Storage

0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code

2934.99.9001

More Info

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#B7B09C11

QC Data

View QC data: current batch, Lot#B7B09C11

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

CHIR-090 is a slow, tight-binding inhibitor of the LpxC deacetylase with a Ki of 4.0 nM for E. coli LpxC.

In vitro activity:

Strongly supporting this notion, growth of LpxH depleted cells (-IPTG) was rescued by exposure to the well-characterized LpxC inhibitor, CHIR-090 in a dose-dependent fashion (Fig 7A and 7B). The concentration of CHIR-090 used here (8–16 μg/ml) was sufficient to block LpxC since this level of exposure dramatically reduces or eliminates LPS production in A. baumannii ATCC19606 (S20 Fig). A similar result was recently reported using the LpxC inhibitor PF-508109 at 32 μg/ml. Furthermore, cells under LpxH depletion conditions in the presence of CHIR-090 had much lower accumulation these pathway intermediates, indicating that the synthesis of these intermediates was blocked by CHIR-090 under these growth conditions (Fig 8A–8F). These data strongly indicate that toxic accumulation of one or more lipid A pathway intermediates underlies the dependence on LpxH for growth of A. baumannii ATCC 19606. Reference: PLoS One. 2016; 11(8): e0160918. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4985137/

In vivo activity:

The in vivo efficacy of colistin and CHIR-090, alone and in combination, was evaluated using a mouse implant model of infection. The results are presented in Fig. 3. Both in the implant and in the spleen, similar log counts were observed for the mice from the control group (treated with DMSO) and the untreated group (treated with 0.9% NaCl) (Fig. 3). For both the implant and spleen, CHIR-090 used as monotherapy resulted in an approximately 2-log10 kill, whereas colistin caused a 3-log10 reduction compared to the counts in the untreated or control group (Fig. 3). The combination of colistin and CHIR-090 resulted in a greater reduction in the number of CFU (up to 4 log10) (Fig. 3). Reference: Antimicrob Agents Chemother. 2017 Jul; 61(7): e02223-16. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5487635/

	Solvent	mg/mL	mM
Solubility
	DMSO	3.8	8.57
	DMF	2.0	4.57

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 437.50 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:

1. Hou F, Chang Y, Huang Z, Han N, Bin L, Deng H, Li Z, Pan Z, Ding L, Gao H, Yang R, Zhi F, Bi Y. Application of LpxC enzyme inhibitor to inhibit some fast-growing bacteria in human gut bacterial culturomics. BMC Microbiol. 2019 Dec 30;19(1):308. doi: 10.1186/s12866-019-1681-6. PMID: 31888576; PMCID: PMC6937742. 2. Richie DL, Takeoka KT, Bojkovic J, Metzger LE 4th, Rath CM, Sawyer WS, Wei JR, Dean CR. Toxic Accumulation of LPS Pathway Intermediates Underlies the Requirement of LpxH for Growth of Acinetobacter baumannii ATCC 19606. PLoS One. 2016 Aug 15;11(8):e0160918. doi: 10.1371/journal.pone.0160918. PMID: 27526195; PMCID: PMC4985137. 3. Tan JH, Vidaillac C, Yam JKH, Chua SL, Givskov M, Yang L. In Vitro and In Vivo Efficacy of an LpxC Inhibitor, CHIR-090, Alone or Combined with Colistin against Pseudomonas aeruginosa Biofilm. Antimicrob Agents Chemother. 2017 Jun 27;61(7):e02223-16. doi: 10.1128/AAC.02223-16. PMID: 28461320; PMCID: PMC5487635.

In vitro protocol:

In vivo protocol:

1. Tan JH, Vidaillac C, Yam JKH, Chua SL, Givskov M, Yang L. In Vitro and In Vivo Efficacy of an LpxC Inhibitor, CHIR-090, Alone or Combined with Colistin against Pseudomonas aeruginosa Biofilm. Antimicrob Agents Chemother. 2017 Jun 27;61(7):e02223-16. doi: 10.1128/AAC.02223-16. PMID: 28461320; PMCID: PMC5487635.

1: Titecat M, Liang X, Lee CJ, Charlet A, Hocquet D, Lambert T, Pagès JM, Courcol R, Sebbane F, Toone EJ, Zhou P, Lemaitre N. High susceptibility of MDR and XDR Gram-negative pathogens to biphenyl-diacetylene-based difluoromethyl-allo-threonyl-hydroxamate LpxC inhibitors. J Antimicrob Chemother. 2016 Jun 20. pii: dkw210. [Epub ahead of print] PubMed PMID: 27330072. 2: Kalinin D, Holl R. Insights into the zinc-dependent deacetylase LpxC: biochemical properties and inhibitor design. Curr Top Med Chem. 2016 Apr 13. [Epub ahead of print] PubMed PMID: 27072691. 3: Vincent IM, Ehmann DE, Mills SD, Perros M, Barrett MP. Untargeted Metabolomics To Ascertain Antibiotic Modes of Action. Antimicrob Agents Chemother. 2016 Mar 25;60(4):2281-91. doi: 10.1128/AAC.02109-15. Print 2016 Apr. PubMed PMID: 26833150; PubMed Central PMCID: PMC4808186. 4: Yao J, Bruhn DF, Frank MW, Lee RE, Rock CO. Activation of Exogenous Fatty Acids to Acyl-Acyl Carrier Protein Cannot Bypass FabI Inhibition in Neisseria. J Biol Chem. 2016 Jan 1;291(1):171-81. doi: 10.1074/jbc.M115.699462. Epub 2015 Nov 13. PubMed PMID: 26567338; PubMed Central PMCID: PMC4697154. 5: Walkup GK, You Z, Ross PL, Allen EK, Daryaee F, Hale MR, O'Donnell J, Ehmann DE, Schuck VJ, Buurman ET, Choy AL, Hajec L, Murphy-Benenato K, Marone V, Patey SA, Grosser LA, Johnstone M, Walker SG, Tonge PJ, Fisher SL. Translating slow-binding inhibition kinetics into cellular and in vivo effects. Nat Chem Biol. 2015 Jun;11(6):416-23. doi: 10.1038/nchembio.1796. Epub 2015 Apr 20. PubMed PMID: 25894085; PubMed Central PMCID: PMC4536915. 6: Oddo A, Holl R. Design and stereoselective synthesis of a C-aryl furanoside as a conformationally constrained CHIR-090 analogue. Carbohydr Res. 2012 Oct 1;359:59-64. doi: 10.1016/j.carres.2012.06.006. Epub 2012 Jun 18. PubMed PMID: 22925765. 7: Caughlan RE, Jones AK, Delucia AM, Woods AL, Xie L, Ma B, Barnes SW, Walker JR, Sprague ER, Yang X, Dean CR. Mechanisms decreasing in vitro susceptibility to the LpxC inhibitor CHIR-090 in the gram-negative pathogen Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2012 Jan;56(1):17-27. doi: 10.1128/AAC.05417-11. Epub 2011 Oct 24. PubMed PMID: 22024823; PubMed Central PMCID: PMC3256010. 8: Mansoor UF, Vitharana D, Reddy PA, Daubaras DL, McNicholas P, Orth P, Black T, Siddiqui MA. Design and synthesis of potent Gram-negative specific LpxC inhibitors. Bioorg Med Chem Lett. 2011 Feb 15;21(4):1155-61. doi: 10.1016/j.bmcl.2010.12.111. Epub 2010 Dec 28. PubMed PMID: 21273067. 9: Cole KE, Gattis SG, Angell HD, Fierke CA, Christianson DW. Structure of the metal-dependent deacetylase LpxC from Yersinia enterocolitica complexed with the potent inhibitor CHIR-090 . Biochemistry. 2011 Jan 18;50(2):258-65. Epub 2010 Dec 20. PubMed PMID: 21171638; PubMed Central PMCID: PMC3070812. 10: Bodewits K, Raetz CR, Govan JR, Campopiano DJ. Antimicrobial activity of CHIR-090, an inhibitor of lipopolysaccharide biosynthesis, against the Burkholderia cepacia complex. Antimicrob Agents Chemother. 2010 Aug;54(8):3531-3. doi: 10.1128/AAC.01600-09. Epub 2010 Jun 1. PubMed PMID: 20516283; PubMed Central PMCID: PMC2916346. 11: Barb AW, Zhou P. Mechanism and inhibition of LpxC: an essential zinc-dependent deacetylase of bacterial lipid A synthesis. Curr Pharm Biotechnol. 2008 Feb;9(1):9-15. Review. PubMed PMID: 18289052; PubMed Central PMCID: PMC3022321. 12: Barb AW, Jiang L, Raetz CR, Zhou P. Structure of the deacetylase LpxC bound to the antibiotic CHIR-090: Time-dependent inhibition and specificity in ligand binding. Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18433-8. Epub 2007 Nov 19. Erratum in: Proc Natl Acad Sci U S A. 2007 Dec 26;104(52):21020. PubMed PMID: 18025458; PubMed Central PMCID: PMC2141794. 13: Barb AW, McClerren AL, Snehelatha K, Reynolds CM, Zhou P, Raetz CR. Inhibition of lipid A biosynthesis as the primary mechanism of CHIR-090 antibiotic activity in Escherichia coli. Biochemistry. 2007 Mar 27;46(12):3793-802. Epub 2007 Mar 3. PubMed PMID: 17335290; PubMed Central PMCID: PMC2709454. 14: McClerren AL, Endsley S, Bowman JL, Andersen NH, Guan Z, Rudolph J, Raetz CR. A slow, tight-binding inhibitor of the zinc-dependent deacetylase LpxC of lipid A biosynthesis with antibiotic activity comparable to ciprofloxacin. Biochemistry. 2005 Dec 20;44(50):16574-83. PubMed PMID: 16342948; PubMed Central PMCID: PMC2742919.

1. Hogan AM, Rahman ASMZ, Motnenko A, Natarajan A, Maydaniuk DT, León B, Batun Z, Palacios A, Bosch A, Cardona ST. Profiling cell envelope-antibiotic interactions reveals vulnerabilities to β-lactams in a multidrug-resistant bacterium. Nat Commun. 2023 Aug 9;14(1):4815. doi: 10.1038/s41467-023-40494-5. PMID: 37558695; PMCID: PMC10412643.