SB-4 is a potent benzoxazole Bone morphogenetic protein 4 (BMP4) signaling agonist with an EC50 value of 73.64nM[1]. SB-4 activates the BMP4 signaling pathway, leading to an increase in the phosphorylation levels of key second messengers (SMAD-1/5/9), thereby activating BMP target genes such as ID1 and ID3[2]. SB-4 has been widely used to promote the differentiation of bone marrow mesenchymal stem cells (BMSCs) into glial cells[3].
In vitro, SB-4 treatment for 48h significantly inhibited viability of AtT20/D16v-F2 cells, with an IC50 value of 39.05μM[4]. Treatment with 200μM SB-4 for 4 days induced the expression levels of Blimp1, Prdm14, Nnose3 and Stella in the epiblast-like cells (EpiLCs)[5]. Treatment with 10μM SB-4 for 21 days promoted osteogenic differentiation of adipose-derived mesenchymal stem cells (ADMSCs), and increased the levels of alkaline phosphatase and osteopontin[6].
In vivo, SB-4 treatment via intraperitoneal injection at a dose of 5mg/kg every 2 days for 12 days mitigated the placental senescence phenotype in Grem1-overexpressing pregnant mice, alleviated placental dysfunction, and reduced the expression of classical senescence markers[7]. A single intraperitoneal injection of SB-4 (5mg/kg) increased the survival rate of mice exposed to lethal radiation (8Gy) during 21 days and promoted the recovery of blood cells[8].
References:
[1] Bradford S T J, Ranghini E J, Grimley E, et al. High-throughput screens for agonists of bone morphogenetic protein (BMP) signaling identify potent benzoxazole compounds[J]. Journal of Biological Chemistry, 2019, 294(9): 3125-3136.
[2] Lin Z B, Zou P, Ma X Y, et al. Metabolic stress-activated endothelial STING rewires the sinusoidal immune niche in MASLD[J]. The Journal of Clinical Investigation, 2026.
[3] Changmeng Z, Hongfei W, Cheung M C H, et al. Revealing the developmental origin and lineage predilection of neural progenitors within human bone marrow via single-cell analysis: implications for regenerative medicine[J]. Genome Medicine, 2023, 15(1): 66.
[4] Xu L, Ning R, Du X, et al. Bone morphogenetic protein signaling agonist SB4 (BMPSB4) inhibits corticotroph pituitary neuroendocrine tumors by activation of autophagy via a BMP4/SMADs-dependent pathway[J]. ACS Pharmacology & Translational Science, 2024, 7(7): 1951.
[5] Tehrani R S H, Sayahpour F A, Esfandiari F. A comparison between BMP4 and SB4 in inducing germ line gene expression pattern during embryonic stem cells differentiation[J]. Differentiation, 2022, 123: 9-17.
[6] Naghshnejad F, Zeynali B, Shabani I, et al. Effects of Bone Morphogenetic Protein Agonist Small Molecule, SB4, on Osteogenic Differentiation of Adipose-Derived Mesenchymal Stem Cells[J]. Journal of Bone Metabolism, 2026, 33(1): 18.
[7] Tian H, Wei Y, Zhang L, et al. Aberrant expression of Gremlin1 induces trophoblast senescence in the placenta of advanced maternal age pregnancy[J]. Journal of Translational Medicine, 2026.
[8] Li Y, Li Y, Zhang B, et al. Single-cell transcriptomics reveals BMP4-BMPR2 signaling promotes radiation resistance in hematopoietic stem cells following injury[J]. Nature Communications, 2025, 16(1): 5470.