Identification of ALK2 inhibitors and their effect on cancer cells

Expert opinion

Cancer is a disease that is still not well understood. Often times, it is found that a protein will over-express or a protein will be inhibited, allowing for this disease to grow and become unmanageable. However, if we can determine which protein is misbehaving, we can develop a chemical compound to try to correct the effects of cancer disease, hopefully leading the patient back to a more normal state.Researching a disease with the hopes of finding treatment involves lots of questions, followed by lots of experiments to answer those questions. Often, research tried to elucidate the pathway and proteins involved in disease onset/progression. In this paper, researchers were interested in investigating bone morphogenetic protein (BMP9) and activin receptor-like kinase 1 and 2 (ALK1 and ALK2) phosphorylation. BMPs have multiple roles. Any alterations to their function can cause a number of different diseases to appear, such as autoimmune and cardiovascular diseases. BMP9 induces ALK1 and ALK2, which leads to phosphorylation of Smad1/5.In this study, the researchers found better, more specific drug targets for inhibiting abnormal ALK2 or BMP9 signaling. How did they do this? What assays did they use? Were the results significantly different from current drugs against this target? This recent publication will answer all these questions and more! Cancer is a disease that is still not well understood. Often times, it is found that a protein will over-express or a protein will be inhibited, allowing for this disease to grow and become unmanageable. However, if we can determine which protein is misbehaving, we can develop a chemical compound to try to correct the effects of cancer disease, hopefully leading the patient back to a more normal state.Researching a disease with the hopes of finding treatment involves lots of questions, followed by lots of experiments to answer those questions. Often, research tried to elucidate the pathway and proteins involved in disease onset/progression. In this paper, researchers were interested in investigating bone morphogenetic protein (BMP9) and activin receptor-like kinase 1 and 2 (ALK1 and ALK2) phosphorylation. BMPs have multiple roles. Any alterations to their function can cause a number of different diseases to appear, such as autoimmune and cardiovascular diseases. BMP9 induces ALK1 and ALK2, which leads to phosphorylation of Smad1/5.In this study, the researchers found better, more specific drug targets for inhibiting abnormal ALK2 or BMP9 signaling. How did they do this? What assays did they use? Were the results significantly different from current drugs against this target? This recent publication will answer all these questions and more!

Abstract

Bone morphogenetic protein 9 (BMP9), a member of the TGF-β superfamily, is considered a regulator of glucose homeostasis as well as a neuronal differentiation factor. BMP9 induces phosphorylation of Smad1/5 through activin receptor-like kinase 1 and 2 (ALK1 and ALK2). Recently, many studies have shown that BMP9 contributes to tumorigenesis, and aberrant ALK2 expression is involved in many diseases. To investigate the role of BMP9-ALK2 signaling in cancer cells, we used TF-1 cells that require granulocyte-macrophage colony-stimulating factor (GM-CSF) for cell proliferation. BMP9 promoted the proliferation of TF-1 cells in media lacking GM-CSF. TF-1 cells overexpressing ALK2 resulted in the autophosphorylation of Smad1/5, leading to consequent increase in cell growth. Through high-throughput screening (HTS), we found two ALK2-specific inhibitors, KRC203 and KRC360, with IC50 values of 0.9 nM and 0.3 nM. These compounds were more potent and specific for the inhibition of ALK2 when compared to LDN193189. In cell-based assays, these compounds effectively inhibited the proliferation and migration of cancer cells induced by ALK2 and BMP9. Therefore, we propose that our compounds are promising candidates for the treatment of cancer or diseases with abnormal ALK2 or BMP9 signaling.