CHZ868 | CHZ-868 | CAS#1895895-38-1 | JAK2 inhibitor

MedKoo Cat#: 407137 | Name: CHZ868

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Description:

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

CHZ868 or CHZ-868 is a potent and selective type II JAK inhibitor which demonstrates activity in JAK inhibitor persistent cells, murine MPN models, and MPN patient samples. CHZ868 showed significant activity in murine MPN models and induced reductions in mutant allele burden not observed with type I JAK inhibitors. CHZ868 stabilizes JAK2 in an inactive conformation. CHZ868 potently suppressed the growth of CRLF2-rearranged human B-ALL cells, abrogated JAK2 signaling, and improved survival in mice with human or murine B-ALL. CHZ868 and dexamethasone synergistically induced apoptosis in JAK2-dependent B-ALLs and further improved in vivo survival compared to CHZ868 alone. CHZ868 may be useful for patients with JAK2-dependent leukemias and other disorders.

Chemical Structure

CHZ868

CAS#1895895-38-1

Theoretical Analysis

MedKoo Cat#: 407137

Name: CHZ868

CAS#: 1895895-38-1

Chemical Formula: C22H19F2N5O2

Exact Mass: 423.1507

Molecular Weight: 423.42

Elemental Analysis: C, 62.41; H, 4.52; F, 8.97; N, 16.54; O, 7.56

Price and Availability

Size	Price	Availability
5mg	USD 120.00	Ready to ship
10mg	USD 190.00	Ready to ship
25mg	USD 350.00	Ready to ship
50mg	USD 650.00	Ready to ship
100mg	USD 950.00	Ready to ship
200mg	USD 1,650.00	Ready to ship

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Related CAS #

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Synonym

CHZ868; CHZ 868; CHZ-868.

IUPAC/Chemical Name

N-(4-((2-((2,4-difluorophenyl)amino)-1,4-dimethyl-1H-benzo[d]imidazol-5-yl)oxy)pyridin-2-yl)acetamide

InChi Key

KQQLBXFPTDVFAJ-UHFFFAOYSA-N

InChi Code

InChI=1S/C22H19F2N5O2/c1-12-19(31-15-8-9-25-20(11-15)26-13(2)30)7-6-18-21(12)28-22(29(18)3)27-17-5-4-14(23)10-16(17)24/h4-11H,1-3H3,(H,27,28)(H,25,26,30)

SMILES Code

CC(NC1=NC=CC(OC2=CC=C3N(C)C(NC4=CC=C(F)C=C4F)=NC3=C2C)=C1)=O

Appearance

White to off-white

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

CHZ868 reverses Type I JAK Inhibitor Persistence and Demonstrates Efficacy in Myeloproliferative Neoplasms.

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#YXM60707

QC Data

View QC data: current batch, Lot#YXM60707

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

CHZ868 is a type II JAK2 inhibitor with an IC50 of 0.17 μM in EPOR JAK2 WT Ba/F3 cell.

In vitro activity:

The activity of CHZ868 to MPL mutant cells was assessed in vitro. CHZ868 potently inhibited the proliferation of 32D cells expressing MPLW515L (Figures 1F-G). CHZ868 treatment abrogated phosphorylation of Y1007/Y1008 in the JAK2 activation loop, consistent with a type II mechanism of action (Figure 1H, Figure S1O). Inhibitor washout studies confirmed that phosphorylation of JAK2 and STAT5 was gradually restored within 4-24 hr after removing CHZ868 (Figure S1U). CHZ868 potently induced apoptosis in JAK2 and MPL mutant cells as reflected by caspase 3 activation (Figure 1I) and by annexin V staining (Figure S1V), and exhibited enhanced killing of JAK2V617F SET2 cells. These findings demonstrate that type II JAK2 inhibition with CHZ868 shows significant activity in JAK2V617F and MPLW515L mutant cells, including potent inhibition of JAK2 and STAT phosphorylation and induction of cell death. Reference: Cancer Cell. 2015 Jul 13;28(1):29-41. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4503933/

In vivo activity:

The efficacy of CHZ868 at inhibiting myeloproliferation was assessed in vivo. CHZ868 dosed at 30-40 mg/kg orally once daily inhibited JAK-STAT signaling in vivo consistent with potent target inhibition (Figure 4A). CHZ868 therapy resulted in significant reduction in the proportion of mutant cells in the bone marrow (Figure 4B). A significant decrease of mutant allele burden in the CD71+Ter119+ erythroid progenitor compartment with CHZ868 was observed as compared to vehicle-treated mice (Figure 4C), consistent with a mutant-biased reduction in erythroid output. These data demonstrate that type II JAK2 inhibition with CHZ868 reduces mutant allele burden in vivo. Reference: Cancer Cell. 2015 Jul 13;28(1):29-41. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4503933/

	Solvent	mg/mL	mM	comments
Solubility
	DMSO	100.0	236.17

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 423.42 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. Wu SC, Li LS, Kopp N, Montero J, Chapuy B, Yoda A, Christie AL, Liu H, Christodoulou A, van Bodegom D, van der Zwet J, Layer JV, Tivey T, Lane AA, Ryan JA, Ng SY, DeAngelo DJ, Stone RM, Steensma D, Wadleigh M, Harris M, Mandon E, Ebel N, Andraos R, Romanet V, Dölemeyer A, Sterker D, Zender M, Rodig SJ, Murakami M, Hofmann F, Kuo F, Eck MJ, Silverman LB, Sallan SE, Letai A, Baffert F, Vangrevelinghe E, Radimerski T, Gaul C, Weinstock DM. Activity of the Type II JAK2 Inhibitor CHZ868 in B Cell Acute Lymphoblastic Leukemia. Cancer Cell. 2015 Jul 13;28(1):29-41. doi: 10.1016/j.ccell.2015.06.005. PMID: 26175414; PMCID: PMC4505625.

In vitro protocol:

In vivo protocol:

1: Li H, Yang M, Lou D. Troxerutin regulates HIF-1α by activating JAK2/STAT3 signaling to inhibit oxidative stress, inflammation, and apoptosis of cardiomyocytes induced by H2 O2. Drug Dev Res. 2022 Apr;83(2):552-563. doi: 10.1002/ddr.21885. Epub 2021 Oct 7. PMID: 34622462. 2: Downes CEJ, McClure BJ, Bruning JB, Page E, Breen J, Rehn J, Yeung DT, White DL. Acquired JAK2 mutations confer resistance to JAK inhibitors in cell models of acute lymphoblastic leukemia. NPJ Precis Oncol. 2021 Aug 10;5(1):75. doi: 10.1038/s41698-021-00215-x. PMID: 34376782; PMCID: PMC8355279. 3: Tvorogov D, Thomas D, Liau NPD, Dottore M, Barry EF, Lathi M, Kan WL, Hercus TR, Stomski F, Hughes TP, Tergaonkar V, Parker MW, Ross DM, Majeti R, Babon JJ, Lopez AF. Accumulation of JAK activation loop phosphorylation is linked to type I JAK inhibitor withdrawal syndrome in myelofibrosis. Sci Adv. 2018 Nov 28;4(11):eaat3834. doi: 10.1126/sciadv.aat3834. PMID: 30498775; PMCID: PMC6261652. 4: Zhang Y, Gao Y, Zhang H, Zhang J, He F, Hnízda A, Qian M, Liu X, Gocho Y, Pui CH, Cheng T, Wang Q, Yang JJ, Zhu X, Liu X. PDGFRB mutation and tyrosine kinase inhibitor resistance in Ph-like acute lymphoblastic leukemia. Blood. 2018 May 17;131(20):2256-2261. doi: 10.1182/blood-2017-11-817510. Epub 2018 Feb 6. PMID: 29434033; PMCID: PMC5958655. 5: Kong X, Sun H, Pan P, Li D, Zhu F, Chang S, Xu L, Li Y, Hou T. How Does the L884P Mutation Confer Resistance to Type-II Inhibitors of JAK2 Kinase: A Comprehensive Molecular Modeling Study. Sci Rep. 2017 Aug 22;7(1):9088. doi: 10.1038/s41598-017-09586-3. PMID: 28831147; PMCID: PMC5567357. 6: Bose P, Abou Zahr A, Verstovsek S. Investigational Janus kinase inhibitors in development for myelofibrosis. Expert Opin Investig Drugs. 2017 Jun;26(6):723-734. doi: 10.1080/13543784.2017.1323871. Epub 2017 May 8. PMID: 28441920. 7: Wu SC, Li LS, Kopp N, Montero J, Chapuy B, Yoda A, Christie AL, Liu H, Christodoulou A, van Bodegom D, van der Zwet J, Layer JV, Tivey T, Lane AA, Ryan JA, Ng SY, DeAngelo DJ, Stone RM, Steensma D, Wadleigh M, Harris M, Mandon E, Ebel N, Andraos R, Romanet V, Dölemeyer A, Sterker D, Zender M, Rodig SJ, Murakami M, Hofmann F, Kuo F, Eck MJ, Silverman LB, Sallan SE, Letai A, Baffert F, Vangrevelinghe E, Radimerski T, Gaul C, Weinstock DM. Activity of the Type II JAK2 Inhibitor CHZ868 in B Cell Acute Lymphoblastic Leukemia. Cancer Cell. 2015 Jul 13;28(1):29-41. doi: 10.1016/j.ccell.2015.06.005. PMID: 26175414; PMCID: PMC4505625. 8: Meyer SC, Keller MD, Chiu S, Koppikar P, Guryanova OA, Rapaport F, Xu K, Manova K, Pankov D, O'Reilly RJ, Kleppe M, McKenney AS, Shih AH, Shank K, Ahn J, Papalexi E, Spitzer B, Socci N, Viale A, Mandon E, Ebel N, Andraos R, Rubert J, Dammassa E, Romanet V, Dölemeyer A, Zender M, Heinlein M, Rampal R, Weinberg RS, Hoffman R, Sellers WR, Hofmann F, Murakami M, Baffert F, Gaul C, Radimerski T, Levine RL. CHZ868, a Type II JAK2 Inhibitor, Reverses Type I JAK Inhibitor Persistence and Demonstrates Efficacy in Myeloproliferative Neoplasms. Cancer Cell. 2015 Jul 13;28(1):15-28. doi: 10.1016/j.ccell.2015.06.006. PMID: 26175413; PMCID: PMC4503933.

1. Kim AR, Ulirsch JC, Wilmes S, Unal E, Moraga I, Karakukcu M, Yuan D, Kazerounian S, Abdulhay NJ, King DS, Gupta N, Gabriel SB, Lander ES, Patiroglu T, Ozcan A, Ozdemir MA, Garcia KC, Piehler J, Gazda HT, Klein DE, Sankaran VG. Functional Selectivity in Cytokine Signaling Revealed Through a Pathogenic EPO Mutation. Cell. 2017 Mar 9;168(6):1053-1064.e15. doi: 10.1016/j.cell.2017.02.026. PMID: 28283061; PMCID: PMC5376096. 2. Meyer LK, Huang BJ, Delgado-Martin C, Roy RP, Hechmer A, Wandler AM, Vincent TL, Fortina P, Olshen AB, Wood BL, Horton TM, Shannon KM, Teachey DT, Hermiston ML. Glucocorticoids paradoxically facilitate steroid resistance in T cell acute lymphoblastic leukemias and thymocytes. J Clin Invest. 2020 Feb 3;130(2):863-876. doi: 10.1172/JCI130189. PMID: 31687977; PMCID: PMC6994137. 3.