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; IC 50 ¼ 23 and 19 nM for JAK2 WT and JAK2 V617F , respectively) within the JAK family (IC 50 ¼ 1280, 520 and 50 nM for JAK1, JK3 and TYK2, respectively) and fms-like tyrosine kinase-3 (FLT3; IC 50 ¼ 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.

Identification of a Dual Inhibitor of Janus Kinase 2 (JAK2) and p70 Ribosomal S6 Kinase1 (S6K1) Pathways

“…3A). Multiple JAK2 inhibitors have been previously reported to show similar results where they directly target JAK2 but increase or do not affect JAK2 phosphorylation levels (44,45). GinA markedly inhibited S6 phosphorylation dose-dependently in both EJ and HCT116 cells (Fig.…”

“…Previous studies have also reported multiple JAK2 inhibitors that maintained or increased the phosphorylation levels of JAK2 (44,45). In addition, inhibitors for other kinases have been shown to not affect the phosphorylation levels of the target kinase, whereas the activity was inhibited by the compounds (51)(52)(53).…”

SB1578, a Novel Inhibitor of JAK2, FLT3, and c-Fms for the Treatment of Rheumatoid Arthritis

“…macrocycles discovered in the S*BIO kinase inhibitor program (30,31). As shown in Supplemental Table I, its potency against JAK2 (IC 50 = 46 nM) was achieved with good selectivity against JAK1 and JAK3 (.60-fold) and 5-fold difference against TYK2 (IC 50 = 230 nM).…”

Characterization of BMS-911543, a functionally selective small-molecule inhibitor of JAK2

“…Studies of this type have ascribed a role for JAK2 dependency in cancer subtypes of breast, prostate, multiple myeloma and Bcell lymphomas. [36][37][38][39] We did not observe inhibitory effects of BMS-911543 in various solid tumor or lymphoma cell lines, including the B-cell lymphoma cell line, KARPAS1106, which is reported to have constitutive JAK2 signaling through genetic inactivation of the pathway negative regulator, SOCS1. 28 Unlike MPNs, our results suggest that persistent STAT3/5 activation does not confer JAK2 dependence in these other cancers, and that the lack of selectivity of the inhibitors utilized towards other JAK family members or kinases outside the family may underlie the observed effects.…”