Design and Synthesis of Pyrimido [4,5-d]pyrimidin-4(3H)-ones as Selective L3MBTL1 Binders

作者：Zhou Hao; Che Xin; Peng Li; Wang Na; Bai Xu^*

来源：Chemical Journal of Chinese Universities, 2016, 37(7): 1293-1301.

DOI：10.7503/cjcu20160203

• Pyrimido[4,5-d]pyrimidin-4(3H)-ones
• Lethal 3 malignant brain tumor 1
• Selective binder

Histone methylation is a key epigenetic mark, and its deregulation is linked to many diseases. Malignant brain tumor (MBT) domain protein is one of the proteins that could read methylated lysine (Kme) of histones. Lethal 3 malignant brain tumor 1 (L3MBTL1), a member of the MBT family, is related to transcriptional repression, erythroid differentiation and tumor formation. Developing a potent and selective inhibitor of L3MBTL1 can help explain the regulatory mechanisms and validate its drugability. UNC669 was reported as the first small molecule ligands for a methyl-lysine binding domain. A series of compounds was synthesized by replacing its aromatic component with pyrimido[4,5-d]pyrimidin-4(3H)-ones. Screening these compounds by AlphaScreen (R) led to a hit compound 8a (IC50 = 1.21 mu mol/L). Exploring 5-position of compound 8a generated three selective and potent L3MBTL1 binders (compounds 8g, 8o and 8p), which showed no significant activity against the other Kme reader proteins in the panel, even its closely related MBT containing proteins, L3MBTL3

• 出版日期2016-7-10
• 单位吉林大学