WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 202571
Description: Pacritinib, also known as SB1518, is a n 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.
MedKoo Cat#: 202571
Name: Pacritinib (SB1518)
Chemical Formula: C28H32N4O3
Exact Mass: 472.24744
Molecular Weight: 472.57868
Elemental Analysis: C, 71.16; H, 6.83; N, 11.86; O, 10.16
Synonym: SB1518; SB 1518; SB-1518; Pacritinib.
IUPAC/Chemical Name: 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[22.214.171.124(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene
SMILES Code: C1(C2=NC(NC3=CC=C(OCCN4CCCC4)C(COC/C=C/COC5)=C3)=NC=C2)=CC5=CC=C1
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. ).
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[126.96.36.199(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, DjÃ¸nne 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.