【紹介文献】
"Discovery of Highly Potent and BMPR2-Selective Kinase Inhibitors Using DNA-Encoded Chemical Library Screening"
J Med Chem. 2023 Feb 9;66(3):2143-2160.
https://pubs.acs.org/doi/10.1021/acs.jmedchem.2c01886
【発表概要】
今回のサイエンスカフェでは、DNA-Encoded Chemical Library (DEL) Screeningを活用した、高選択的BMPR2阻害薬の発見に関する論文を紹介します。本論文では、>109 の規模からなる “unbiased” と “kinase-biased” DELをBMPR2に対してスクリーニングすることで、高活性・高選択的、かつ代謝安定性にも優れたリードライクな阻害薬を取得することに成功しています。その他、最新のDEL技術について紹介いたします。
【Summary】
In this paper, by screening 4.17 billion “unbiased” and “kinase-biased” DNA-encoded chemical library molecules, they identified hits CDD-1115 and CDD-1431, respectively, that were low-nanomolar selective kinase inhibitors of BMPR2. Structure−activity relationship studies addressed metabolic lability and high-molecular-weight issues, resulting in potent and BMPR2-selective inhibitor analogs CDD-1281 (IC50 = 1.2 nM) and CDD-1653 (IC50 = 2.8 nM), respectively. This study demonstrates that DNA-encoded chemistry technology (DEC-Tec) is reliable for identifying novel first-in-class, highly potent, and selective kinase inhibitors.
(2023.4.20 Shonan iPark Science Cafe 144th)
