生物活性

• 描述The bone morphogenetic protein (BMP) signal transduction pathway is a subset of the larger TGF-β signaling family, which includes 7 type I receptors, 5 type II receptors, and over 30 ligands of the BMP, TGF-β, activin, and growth and differentiation factor (GDF) ligand families^[2]. LDN-214117 is a high degree of selectivity inhibitor for the BMP type I receptor kinase ALK2 with IC50 value of 24 nM. LDN-214117 also inhibits the activity of BMP6 and TGFβ with IC50 values of 67 nM and 14.65 μM, respectively (measured by ligand induced transcriptional assay)^[1]. In vitro, LDN-214117 inhibited ACR1 wild-type cells SU-DIPG-VI and QCTB-R059 with GI50 values of 5.38 μM and 8.27 μM, respectively. LDN-214117 also inhibited cell viability of the ACVR1 mutant cells HSJD-DIPG-007(R206H), SU-DIPG-IV(G238V) and HSJD-DIPG-018(R258G) with GI50 values of 1.57 μM, 6.23 μM and 16.38 μM, respectively. Treatment DIPG cell lines SU-DIPG-VI and HSJD-DIPG-IV with 0.1 μM LDN-214117 for 4h inhibited phosphor-SMAD1/5/8 and the downstream effector ID1^[3]. In addition, treatment the lung carcinoma cell line LCLC-103H with LDN-214117 at concentration of 5 μM significantly hindered the migration of LCLC-103H cells into the wound area, reaching relative wound density of only 50% in 48h by inhibition of BMP signaling^[4]. In vivo, the bioavailability (F) and well-tolerance level of LDN-214117 was 0.75 and 25 mg/kg, respectively. Oral administration of LD-214117 at 25 mg/kg for 28 days extended survival in immunodeprived mice bearing orthotopic xenografts of H3.3K27M, ACVR1R206H mutant HSJDDIPG-007 cells^[3].