Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA.
Proc Natl Acad Sci U S A. 2012 Aug 28;109(35):14019-23. doi: 10.1073/pnas.1212545109. Epub 2012 Aug 13.
Molecules that control the lineage commitment of hematopoietic stem cells (HSCs) may allow the expansion of enriched progenitor populations for both research and therapeutic uses. In an effort to better understand and control the differentiation of HSCs to megakaryocytes, we carried out an image-based screen of a library of 50,000 heterocycles using primary human CD34(+) cells. A class of naphthyridinone derivatives was identified that induces the differentiation of common myeloid progenitors (CMP) to megakaryocytes. Kinase profiling and subsequent functional assays revealed that these compounds act through inhibition of platelet-derived growth factor receptor (PDGFR) signaling in CMPs. Such molecules may ultimately have clinical utility in the treatment of thrombocytopenia.
控制造血干细胞（HSCs）谱系定向的分子可能允许为研究和治疗用途扩展丰富的祖细胞群体。为了更好地理解和控制 HSCs 向巨核细胞的分化，我们使用原代人 CD34(+)细胞对 50000 个杂环文库进行了基于图像的筛选。鉴定出一类萘啶酮衍生物，可诱导共同髓系祖细胞（CMP）向巨核细胞分化。激酶分析和随后的功能测定表明，这些化合物通过抑制 CMP 中的血小板衍生生长因子受体（PDGFR）信号传导起作用。此类分子最终可能在治疗血小板减少症方面具有临床应用价值。
