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MedKoo Cat#: 202571 | Name: Pacritinib (SB1518)
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Description:

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

Pacritinib, also known as SB1518, is an orally bioavailable inhibitor of Janus kinase 2 (JAK2) and the JAK2 mutant JAK2V617F with potential antineoplastic activity. Pacritinib competes with JAK2 for ATP binding, which may result in inhibition of JAK2 activation, inhibition of the JAK-STAT signaling pathway, and so caspase-dependent apoptosis. JAK2 is the most common mutated gene in bcr-abl-negative myeloproliferative disorders; the JAK2V617F gain-of-function mutation involves a valine-to-phenylalanine modification at position 617. The JAK-STAT signaling pathway is a major mediator of cytokine activity.

Chemical Structure

Pacritinib (SB1518)
Pacritinib (SB1518)
CAS#937272-79-2 (free base)

Theoretical Analysis

MedKoo Cat#: 202571

Name: Pacritinib (SB1518)

CAS#: 937272-79-2 (free base)

Chemical Formula: C28H32N4O3

Exact Mass: 472.2474

Molecular Weight: 472.58

Elemental Analysis: C, 71.16; H, 6.83; N, 11.86; O, 10.16

Price and Availability

Size Price Availability Quantity
10mg USD 110.00 Ready to ship
25mg USD 220.00 Ready to ship
50mg USD 385.00 Ready to ship
100mg USD 685.00 Ready to ship
200mg USD 1,250.00 Ready to ship
500mg USD 2,650.00 Ready to ship
1g USD 3,650.00 Ready to ship
2g USD 6,250.00 Ready to ship
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Related CAS #
937272-79-2 (free base) 1228923-42-9 (citrate) 1228923-43-0 (HCl)
Synonym
SB1518; SB 1518; SB-1518; Pacritinib.
IUPAC/Chemical Name
11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene
InChi Key
HWXVIOGONBBTBY-ONEGZZNKSA-N
InChi Code
InChI=1S/C28H32N4O3/c1-2-13-32(12-1)14-17-35-27-9-8-25-19-24(27)21-34-16-4-3-15-33-20-22-6-5-7-23(18-22)26-10-11-29-28(30-25)31-26/h3-11,18-19H,1-2,12-17,20-21H2,(H,29,30,31)/b4-3+
SMILES Code
C1(C2=NC(NC3=CC=C(OCCN4CCCC4)C(COC/C=C/COC5)=C3)=NC=C2)=CC5=CC=C1
Appearance
Solid powder
Purity
>98%
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
>5 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
    SB1518 is an innovative pyrimidine-based macrocycle that shows a unique kinase profile with selective inhibition of Janus Kinase-2 (JAK2; IC(50)=23 and 19 nM for JAK2(WT) and JAK2(V617F), respectively) within the JAK family (IC(50)=1280, 520 and 50 nM for JAK1, JK3 and TYK2, respectively) and fms-like tyrosine kinase-3 (FLT3; IC(50)=22 nM). SB1518 shows potent effects on cellular JAK/STAT pathways, inhibiting tyrosine phosphorylation on JAK2 (Y221) and downstream STATs. As a consequence SB1518 has potent anti-proliferative effects on myeloid and lymphoid cell lines driven by mutant or wild-type JAK2 or FLT3, resulting from cell cycle arrest and induction of apoptosis. SB1518 has favorable pharmacokinetic properties after oral dosing in mice, is well tolerated and significantly reduces splenomegaly and hepatomegaly in a JAK2(V617F)-driven disease model. SB1518 dose-dependently inhibits intra-tumor JAK2/STAT5 signaling, leading to tumor growth inhibition in a subcutaneous model generated with SET-2 cells derived from a JAK2(V617F) patient with megakaryoblastic leukemia. Moreover, SB1518 is active against primary erythroid progenitor cells sampled from patients with myeloproliferative disease. In summary, SB1518 has a unique profile and is efficacious and well tolerated in JAK2-dependent models. These favorable properties are now being confirmed in clinical studies in patients with myelofibrosis and lymphoma. ( source: Leukemia. 2011 Nov;25(11):1751-9. ).        
Biological target:
Pacritinib (SB1518) is a potent inhibitor of both wild-type JAK2 (IC50=23 nM) and JAK2V617F mutant (IC50=19 nM). Pacritinib also inhibits FLT3 (IC50=22 nM) and its mutant FLT3D835Y (IC50=6 nM).
In vitro activity:
Pacritinib is in development as a treatment for myelofibrosis. In the previous kinome-wide screen, pacritinib was found to suppress phosphorylation of two other kinases of potential interest in myeloid diseases, specifically IRAK1 (IC50 = 13.6 nM) and CSF1R (IC50 = 46 nM). Pacritinib also inhibited the growth of FLT3-ITD–positive cells (MOLM-13, MOLM-14) at IC50 values of ~32 nM and 61 nM, respectively, and JAK3 mutation-positive cells (CMK) at an IC50 value of 262 nM. In addition, pacritinib inhibits FLT3 signaling in AML cell lines with the highest potency against cells harboring FLT3-ITD mutations. In addition, pacritinib inhibited growth of cell lines harboring various genetic mutations at IC50 values ranging from ~100 to ~500 nM for cell lines Kasumi-1, SKNO-1, OCI-AML5, GDM-1, THP1, and HL-60, and ranging from ~750 to ~1500 nM for cell lines. We showed that pacritinib has potent inhibitory effects on AML cell lines and primary AML samples harboring a wide variety of genetic mutations. Therefore, further clinical exploration of IRAK1 as a target for intervention with pacritinib and newer more specific agents is justified in AML and other neoplastic disorders associated with IRAK pathway activation Leukemia. 2018 Nov; 32(11): 2374–2387.Published online 2018 Mar 29. doi: 10.1038/s41375-018-0112-2 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6558520/
In vivo activity:
The efficacy of pacritinib, a JAK2 inhibitor currently in phase 3 trials was tested.The efficacy of pacritinib was tested in vivo in pharmacokinetic analyses, liver microsome analyses, and Kaplan-Meier survival studies. In vivo, systemic treatment with pacritinib demonstrated blood-brain barrier penetration and led to improved overall median survival in combination with TMZ, in mice orthotopically xenografted with an aggressive recurrent GBM BTIC culture. Thirty-two mice were xenografted with 5 x 104 BT147 cells each and randomized into treatment cohorts. Treatment began one week post cell implantation with mice randomized to vehicle (Ora-Plus), pacritinib (100mg/kg), TMZ (30mg/kg), or pacritinib (100 mg/kg) + TMZ (30 mg/kg) cohorts. Mice were treated for five weeks, three times per week for a total of 15 treatments. The combination of pacritinib and TMZ provided a significant improvement to overall median survival. In vivo, systemic treatment with pacritinib was tolerated and demonstrated favourable pharmacokinetic properties. While pacritinib was found to be unstable in mouse liver microsomes, the drug was stable in human liver microsomes. Despite the rapid metabolism of pacritinib, there was a significant increase in overall median survival in combination with TMZ in mice orthotopically xenografted with an aggressive recurrent GBM BTIC culture. These results suggest that benefits observed in our mouse model may hold further promise in humans, where the drug is not as rapidly metabolized and has promising safety profiles. PLoS One. 2017; 12(12): e0189670. Published online 2017 Dec 18. doi: 10.1371/journal.pone.0189670 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5734728/
Solvent mg/mL mM
Solubility
DMSO 5.0 10.60
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 472.58 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.

Recalculate based on batch purity %
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. Hosseini MM, Kurtz SE, Abdelhamed S, Mahmood S, Davare MA, Kaempf A, Elferich J, McDermott JE, Liu T, Payne SH, Shinde U, Rodland KD, Mori M, Druker BJ, Singer JW, Agarwal A. Inhibition of interleukin-1 receptor-associated kinase-1 is a therapeutic strategy for acute myeloid leukemia subtypes. Leukemia. 2018 Nov;32(11):2374-2387. doi: 10.1038/s41375-018-0112-2. Epub 2018 Mar 29. PMID: 29743719; PMCID: PMC6558520. 2. Jensen KV, Cseh O, Aman A, Weiss S, Luchman HA. The JAK2/STAT3 inhibitor pacritinib effectively inhibits patient-derived GBM brain tumor initiating cells in vitro and when used in combination with temozolomide increases survival in an orthotopic xenograft model. PLoS One. 2017 Dec 18;12(12):e0189670. doi: 10.1371/journal.pone.0189670. PMID: 29253028; PMCID: PMC5734728. 3. Jensen KV, Cseh O, Aman A, Weiss S, Luchman HA. The JAK2/STAT3 inhibitor pacritinib effectively inhibits patient-derived GBM brain tumor initiating cells in vitro and when used in combination with temozolomide increases survival in an orthotopic xenograft model. PLoS One. 2017 Dec 18;12(12):e0189670. doi: 10.1371/journal.pone.0189670. PMID: 29253028; PMCID: PMC5734728. 4. Hosseini MM, Kurtz SE, Abdelhamed S, Mahmood S, Davare MA, Kaempf A, Elferich J, McDermott JE, Liu T, Payne SH, Shinde U, Rodland KD, Mori M, Druker BJ, Singer JW, Agarwal A. Inhibition of interleukin-1 receptor-associated kinase-1 is a therapeutic strategy for acute myeloid leukemia subtypes. Leukemia. 2018 Nov;32(11):2374-2387. doi: 10.1038/s41375-018-0112-2. Epub 2018 Mar 29. PMID: 29743719; PMCID: PMC6558520.
In vitro protocol:
1. Hosseini MM, Kurtz SE, Abdelhamed S, Mahmood S, Davare MA, Kaempf A, Elferich J, McDermott JE, Liu T, Payne SH, Shinde U, Rodland KD, Mori M, Druker BJ, Singer JW, Agarwal A. Inhibition of interleukin-1 receptor-associated kinase-1 is a therapeutic strategy for acute myeloid leukemia subtypes. Leukemia. 2018 Nov;32(11):2374-2387. doi: 10.1038/s41375-018-0112-2. Epub 2018 Mar 29. PMID: 29743719; PMCID: PMC6558520. 2. Jensen KV, Cseh O, Aman A, Weiss S, Luchman HA. The JAK2/STAT3 inhibitor pacritinib effectively inhibits patient-derived GBM brain tumor initiating cells in vitro and when used in combination with temozolomide increases survival in an orthotopic xenograft model. PLoS One. 2017 Dec 18;12(12):e0189670. doi: 10.1371/journal.pone.0189670. PMID: 29253028; PMCID: PMC5734728.
In vivo protocol:
1. Jensen KV, Cseh O, Aman A, Weiss S, Luchman HA. The JAK2/STAT3 inhibitor pacritinib effectively inhibits patient-derived GBM brain tumor initiating cells in vitro and when used in combination with temozolomide increases survival in an orthotopic xenograft model. PLoS One. 2017 Dec 18;12(12):e0189670. doi: 10.1371/journal.pone.0189670. PMID: 29253028; PMCID: PMC5734728. 2. Hosseini MM, Kurtz SE, Abdelhamed S, Mahmood S, Davare MA, Kaempf A, Elferich J, McDermott JE, Liu T, Payne SH, Shinde U, Rodland KD, Mori M, Druker BJ, Singer JW, Agarwal A. Inhibition of interleukin-1 receptor-associated kinase-1 is a therapeutic strategy for acute myeloid leukemia subtypes. Leukemia. 2018 Nov;32(11):2374-2387. doi: 10.1038/s41375-018-0112-2. Epub 2018 Mar 29. PMID: 29743719; PMCID: PMC6558520.
1: Sunkara PK, Chaganty S, Ramakrishna K. Development and validation of an LC- MSMS method for the quantitation of pacritinib; application of kinetics in rabbits. J Pharmacol Toxicol Methods. 2024 Jul 26;129:107547. doi: 10.1016/j.vascn.2024.107547. Epub ahead of print. PMID: 39069107. 2: Hunter AM, Bose P. Advances with janus kinase inhibitors for the treatment of myeloproliferative neoplasms: an update of the literature. Expert Opin Pharmacother. 2024 Aug 1:1-14. doi: 10.1080/14656566.2024.2385729. Epub ahead of print. PMID: 39067001. 3: Pidala JA, Holtan SG, Walton K, Kim J, Cao B, Elmariah H, Mishra A, Bejanyan N, Nishihori T, Khimani F, Perez LE, Faramand RG, Davila ML, McSain S, Pleskow J, Baron J, Anasetti C, Moran Segura CM, Weisdorf DJ, Blazar BR, Miller JS, Bachanova V, El Jurdi N, Betts BC. JAK2/mTOR Inhibition Fails to Prevent Acute GVHD Despite Reduced Th1/Th17 cells: Final Phase II Trial Results. Blood. 2024 Jul 24:blood.2024024789. doi: 10.1182/blood.2024024789. Epub ahead of print. PMID: 39046783. 4: Gagelmann N, Bose P, Gupta V, McLornan DP, Vachhani P, Al-Ali HK, Ali H, Treskes P, Buckley S, Roman-Torres K, Scott B. Consistency of Spleen and Symptom Reduction Regardless of Cytopenia in Patients With Myelofibrosis Treated With Pacritinib. Clin Lymphoma Myeloma Leuk. 2024 Jul 2:S2152-2650(24)00246-5. doi: 10.1016/j.clml.2024.06.012. Epub ahead of print. PMID: 39034203. 5: Regua AT, Bindal S, Najjar MK, Zhuang C, Khan M, Arrigo ABJ, Gonzalez AO, Zhang XR, Zhu JJ, Watabe K, Lo HW. Dual inhibition of the TrkA and JAK2 pathways using entrectinib and pacritinib suppresses the growth and metastasis of HER2-positive and triple-negative breast cancers. Cancer Lett. 2024 Aug 10;597:217023. doi: 10.1016/j.canlet.2024.217023. Epub 2024 Jun 7. PMID: 38852701. 6: Miao Y, Virtanen A, Zmajkovic J, Hilpert M, Skoda RC, Silvennoinen O, Haikarainen T. Functional and Structural Characterization of Clinical-Stage Janus Kinase 2 Inhibitors Identifies Determinants for Drug Selectivity. J Med Chem. 2024 Jun 27;67(12):10012-10024. doi: 10.1021/acs.jmedchem.4c00197. Epub 2024 Jun 6. PMID: 38843875; PMCID: PMC11215726. 7: Zhao Y, Zhang X, Ding X, Wang Y, Li Z, Zhao R, Cheng HE, Sun Y. Efficacy and safety of FLT3 inhibitors in monotherapy of hematological and solid malignancies: a systemic analysis of clinical trials. Front Pharmacol. 2024 May 17;15:1294668. doi: 10.3389/fphar.2024.1294668. PMID: 38828446; PMCID: PMC11140126. 8: Kim KM, Hwang NH, Hyun JS, Shin D. Recent Advances in IRAK1: Pharmacological and Therapeutic Aspects. Molecules. 2024 May 9;29(10):2226. doi: 10.3390/molecules29102226. PMID: 38792088; PMCID: PMC11123835. 9: Tiribelli M, Morelli G, Bonifacio M. Advances in pharmacotherapy for myelofibrosis: what is the current state of play? Expert Opin Pharmacother. 2024 Apr;25(6):743-754. doi: 10.1080/14656566.2024.2354461. Epub 2024 May 14. PMID: 38738513. 10: Cuenca-Zamora EJ, Guijarro-Carrillo PJ, López-Poveda MJ, Morales ML, Lozano ML, Gonzalez-Conejero R, Martínez C, Teruel-Montoya R, Ferrer-Marín F. miR-146a-/- mice model reveals that NF-κB inhibition reverts inflammation-driven myelofibrosis-like phenotype. Am J Hematol. 2024 Jul;99(7):1326-1337. doi: 10.1002/ajh.27322. Epub 2024 Apr 22. PMID: 38646919. 11: Bruzzese A, Martino EA, Labanca C, Mendicino F, Lucia E, Olivito V, Zimbo A, Fragliasso V, Neri A, Morabito F, Vigna E, Gentile M. Momelotinib in myelofibrosis. Expert Opin Pharmacother. 2024 Apr;25(5):521-528. doi: 10.1080/14656566.2024.2343780. Epub 2024 Apr 18. PMID: 38623844. 12: Verstovsek S, Mesa R, Talpaz M, Kiladjian JJ, Harrison CN, Oh ST, Vannucchi AM, Rampal R, Scott BL, Buckley SA, Craig AR, Roman-Torres K, Mascarenhas JO. Erratum to: Retrospective analysis of pacritinib in patients with myelofibrosis and severe thrombocytopenia. Haematologica. 2024 Apr 1;109(4):3010. doi: 10.3324/haematol.2023.284815. Erratum for: doi: 10.3324/haematol.2021.279415. PMID: 38562076; PMCID: PMC10988197. 13: Keenan C, Albeituni S, Oak N, Stroh A, Tillman HS, Wang Y, Freeman BB 3rd, Alemán-Arteaga S, Meyer LK, Woods R, Verbist KC, Zhou Y, Cheng C, Nichols KE. Differential effects of itacitinib, fedratinib, and ruxolitinib in mouse models of hemophagocytic lymphohistiocytosis. Blood. 2024 Jun 6;143(23):2386-2400. doi: 10.1182/blood.2023021046. PMID: 38446698. 14: Rao X, Qiao Z, Yang Y, Deng Y, Zhang Z, Yu X, Guo X. Unveiling Epigenetic Vulnerabilities in Triple-Negative Breast Cancer through 3D Organoid Drug Screening. Pharmaceuticals (Basel). 2024 Feb 8;17(2):225. doi: 10.3390/ph17020225. PMID: 38399440; PMCID: PMC10892330. 15: Acharya B, Saha D, Armstrong D, Jabali B, Hanafi M, Herrera-Rueda A, Lakkaniga NR, Frett B. Kinase inhibitor macrocycles: a perspective on limiting conformational flexibility when targeting the kinome with small molecules. RSC Med Chem. 2023 Dec 12;15(2):399-415. doi: 10.1039/d3md00457k. PMID: 38389874; PMCID: PMC10880908. 16: Wu Y, Wang V, Yarchoan R. Pacritinib inhibits proliferation of primary effusion lymphoma cells and production of viral interleukin-6 induced cytokines. Sci Rep. 2024 Feb 19;14(1):4125. doi: 10.1038/s41598-024-54453-7. PMID: 38374336; PMCID: PMC10876599. 17: Zammarchi F, Havenith KE, Sachini N, Janghra N, Chivers S, Idusogie E, Gaudio E, Tarantelli C, Bertelli F, Santos K, Tyrer P, Corbett S, Spriano F, Golino G, Cascione L, Bertoni F, Hartley JA, van Berkel PH. ADCT-602, a Novel PBD Dimer-containing Antibody-Drug Conjugate for Treating CD22-positive Hematologic Malignancies. Mol Cancer Ther. 2024 Apr 2;23(4):520-531. doi: 10.1158/1535-7163.MCT-23-0506. PMID: 38324336; PMCID: PMC10985467. 18: Handa S, Farina KA, Becker M, Kelly B, Yu A, Feld J, Tremblay D, Marcellino BK, Salib C, Mascarenhas J, Shih AH. Discontinuation Syndrome With JAK2 Selective Agents: Case Presentation and Mechanistic Insights. JCO Precis Oncol. 2024 Jan;8:e2300234. doi: 10.1200/PO.23.00234. PMID: 38295318; PMCID: PMC10843369. 19: Duminuco A, Chifotides HT, Giallongo S, Giallongo C, Tibullo D, Palumbo GA. ACVR1: A Novel Therapeutic Target to Treat Anemia in Myelofibrosis. Cancers (Basel). 2023 Dec 28;16(1):154. doi: 10.3390/cancers16010154. PMID: 38201581; PMCID: PMC10778144. 20: Tefferi A, Pardanani A, Gangat N. Momelotinib expands the therapeutic armamentarium for myelofibrosis: Impact on hierarchy of treatment choices. Am J Hematol. 2024 Feb;99(2):300-308. doi: 10.1002/ajh.27163. Epub 2024 Jan 2. PMID: 38164985.
1. Dai Z, Chen J, Chang Y, Christiano AM. Selective inhibition of JAK3 signaling is sufficient to reverse alopecia areata. JCI Insight. 2021 Apr 8;6(7):142205. doi: 10.1172/jci.insight.142205. PMID: 33830087.