Pacritinib (SB1518)
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MedKoo CAT#: 202571

CAS#: 937272-79-2

Description: 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

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Pacritinib (SB1518)
CAS# 937272-79-2

Theoretical Analysis

MedKoo Cat#: 202571
Name: Pacritinib (SB1518)
CAS#: 937272-79-2
Chemical Formula: C28H32N4O3
Exact Mass: 472.24744
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
25.0mg USD 150.0 Ready to ship
50.0mg USD 250.0 Ready to ship
100.0mg USD 450.0 Ready to ship
200.0mg USD 650.0 Ready to ship
500.0mg USD 1150.0 Ready to ship
1.0g USD 1950.0 Ready to ship
2.0g USD 3250.0 Ready to ship
5.0g USD 5250.0 2 Weeks
10.0g USD 8250.0 2 Weeks
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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

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/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 5.0 10.6

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.

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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.

1: Hart S, Goh KC, Novotny-Diermayr V, Hu CY, Hentze H, Tan YC, Madan B, Amalini C, Loh YK, Ong LC, William AD, Lee A, Poulsen A, Jayaraman R, Ong KH, Ethirajulu K, Dymock BW, Wood JW. SB1518, a novel macrocyclic pyrimidine-based JAK2 inhibitor for the treatment of myeloid and lymphoid malignancies. Leukemia. 2011 Nov;25(11):1751-9. doi: 10.1038/leu.2011.148. Epub 2011 Jun 21. PubMed PMID: 21691275.

2: William AD, Lee AC, Blanchard S, Poulsen A, Teo EL, Nagaraj H, Tan E, Chen D, Williams M, Sun ET, Goh KC, Ong WC, Goh SK, Hart S, Jayaraman R, Pasha MK, Ethirajulu K, Wood JM, Dymock BW. Discovery of the macrocycle 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 (SB1518), a potent Janus kinase 2/fms-like tyrosine kinase-3 (JAK2/FLT3) inhibitor for the treatment of myelofibrosis and lymphoma. J Med Chem. 2011 Jul 14;54(13):4638-58. Epub 2011 Jun 15. PubMed PMID: 21604762.

3: Biffa D, Skjerve E, Oloya J, Bogale A, Abebe F, Dahle U, Bohlin J, Djønne B. Molecular characterization of Mycobacterium bovis isolates from Ethiopian cattle. BMC Vet Res. 2010 May 27;6:28. PubMed PMID: 20507576; PubMed Central PMCID: PMC2886024.



Additional Information

 
 
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. ).