SB1518, a novel macrocyclic pyrimidine-based JAK2 inhibitor for the treatment of myeloid and lymphoid malignancies.

Abstract

SB1518 is an innovative pyrimidine-based macrocycle that shows a unique kinase profile with selective inhibition of Janus Kinase-2 (JAK2; IC50=23 and 19 nM for JAK2(WT) and JAK2(V617F), respectively) within the JAK family (IC50=1280, 520 and 50 nM for JAK1, JK3 and TYK2, respectively) and fms-like tyrosine kinase-3 (FLT3; IC50=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.

• Authors: S Hart, K C Goh, V Novotny-Diermayr, C Y Hu, H Hentze, Y C Tan, B Madan, C Amalini, Y K Loh, L C Ong, A D William, A Lee, A Poulsen, R Jayaraman, K H Ong, K Ethirajulu, B W Dymock, J W Wood
• Journal: Leukemia (Leukemia) Vol. 25 Issue 11 Pg. 1751-9 (Nov 2011) ISSN: 1476-5551 [Electronic] England
• PMID: 21691275 (Publication Type: Journal Article)

Chemical References

• 11-(2-pyrrolidin-1-ylethoxy)-14,19-dioxa-5,7,26-triazatetracyclo(19.3.1.1(2,6).1(8,12))heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene
• Antineoplastic Agents
• Bridged-Ring Compounds
• Pyrimidines
• Janus Kinase 2

Topics

• Antineoplastic Agents (pharmacology, therapeutic use)
• Blotting, Western
• Bridged-Ring Compounds (pharmacology, therapeutic use)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Flow Cytometry
• Humans
• Janus Kinase 2 (antagonists & inhibitors)
• Leukemia, Lymphoid (drug therapy)
• Leukemia, Myeloid (drug therapy)
• Pyrimidines (pharmacology, therapeutic use)
• Signal Transduction