Description
Activation of bone morphogenetic protein (BMP) type I receptors, also known as activin receptor-like kinases (ALK1-7), leads to the assembly of SMAD complexes, which translocate to the nucleus to induce transcriptional activation important for normal development and tissue repair. K02288 is a 2-aminopyridine-based inhibitor of ALK1 and ALK2 with IC
50 values of 1.8 and 1.1 nM, respectively. It is less selective for ALK3, 4, 5, and 6 subtypes and the type II BMP receptor ActRIIA, demonstrating IC
50 values of 34.4, 302, 321, 6.4, and 220 nM, respectively. K02288 can prevent BMP4-induced SMAD1/5/8 pathway activation
in vitro (IC
50 = 100 nM) without affecting TGF-β signaling. Furthermore, at 8-10 μM, K02288 has been used to induce the dorsalization of zebrafish embryos. Through specific inhibition of BMP signaling, this compound can be used to research stem cell biology and disease models of musculoskeletal dysplasia and cancer.
Uses
K02288 is a potent and selective type 1 BMP (bone morphogenetic protein) receptor inhibitor with in vitro activity against ALK-2 (activin receptor-like kinase-2) at low nanomolar concentrations. K02288 also inhibits the BMP-induced Smad pathway without affecting TGF-β signaling and induces dorsalization of zebrafish embryos.
Biochem/physiol Actions
K02288 is functionally similar to dorsomorphin, which is known to be the first small-molecule for BMP signaling inhibition.BMP signalling is associated with many important physiological processes. It acts a central regulator of developmental processes such as organogenesis, gastrulation, mesoderm induction and endochondral bone formation. BMP signals are also related to diseases including pulmonary hypertension, juvenile polyposis syndrome, fibrodysplasia ossificans progressiva and hereditary hemorrhagic telangiectasia syndrome. BMP signaling inhibition might serve as a tool to study its role in other biological processes.
References
[1] sanvitale ce, kerr g, chaikuad a, ramel mc, mohedas ah, reichert s, wang y, triffitt jt, cuny gd, yu pb, hill cs, bullock an. a new class of small molecule inhibitor of bmp signaling. plos one. 2013 apr 30;8(4):e62721.
