tcsc0864 Ruxolitinib

Ruxolitinib is the first potent, selective JAK1/2 inhibitor to enter the clinic with IC₅₀ of 3.3 nM/2.8 nM in cell-free assays, and has > 130-fold selectivity for JAK1/2 versus JAK3.

IC50 & Target: IC50: 3.3 nM (JAK1), 2.8 nM (JAK2)

In Vitro: Ruxolitinib potently and selectively inhibits JAK2V617F-mediated signaling and proliferation, markedly increases apoptosis in a dose dependent manner, and at 64 nM results in a doubling of cells with depolarized mitochondria in Ba/F3 cells. Ruxolitinib demonstrates remarkable potency against erythroid colony formation with IC₅₀ of 67 nM, and inhibits proliferating of erythroid progenitors from normal donors and polycythemia vera patients with IC₅₀ values of 407 nM and 223 nM, respectively^[1].

In Vivo: Ruxolitinib (180 mg/kg, orally, twice a day) results in survive rate of greater than 90% by day 22 and markedly reduces splenomegaly and circulating levels of inflammatory cytokines, and preferentially eliminated neoplastic cells, resulting in significantly prolonged survival without myelosuppressive or immunosuppressive effects in a JAK2V617F-driven mouse model^[1]. In the Ruxolitinib group, the primary end point is reached in 41.9% of patients, as compared with 0.7% in the placebo group in the double-blind trial of myelofibrosis. Ruxolitinib results in maintaining of reduction in spleen volume and improvement of 50% or more in the total symptom score^[2]. Ruxolitinib (15 mg twice daily) treatment leads a total of 28% of the patients to have at least a 35% reduction in spleen volume at week 48 in patients with myelofibrosis, as compared with 0% in the group receiving the best available therapy. The mean palpable spleen length has decreased by 56% with Ruxolitinib but has increased by 4% with the best available therapy at week 48. Patients in the ruxolitinib group has an improvement in overall quality-of-life measures and a reduction in symptoms associated with myelofibrosis^[3].