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MSRC Mass Spectrometry Research and Development

The structure-activity relationships of L3MBTL3 inhibitors: flexibility of the dimer interface.

AUTHORS

Camerino MAMichelle A , Zhong N Nan , Dong A Aiping , Dickson BM Bradley M , James LI Lindsey I , Baughman BM Brandi M , Norris JL Jacqueline L , Kireev DB Dmitri B , Janzen WP William P , Arrowsmith CH Cheryl H , Frye SV Stephen V . MedChemComm. 2013 11 ; 4(11). 1501-1507

ABSTRACT

We recently reported the discovery of UNC1215, a potent and selective chemical probe for the L3MBTL3 methyllysine reader domain. In this article, we describe the development of structure-activity relationships (SAR) of a second series of potent L3MBTL3 antagonists which evolved from the structure of the chemical probe UNC1215. These compounds are selective for L3MBTL3 against a panel of methyllysine reader proteins, particularly the related MBT family proteins, L3MBTL1 and MBTD1. A co-crystal structure of L3MBTL3 and one of the most potent compounds suggests that the L3MBTL3 dimer rotates about the dimer interface to accommodate ligand binding.

We recently reported the discovery of UNC1215, a potent and selective chemical probe for the L3MBTL3 methyllysine reader domain. In this article, we describe the development of structure-activity relationships (SAR) of a second series of potent L3MBTL3 antagonists which evolved from the structure of the chemical probe UNC1215. These compounds are selective for L3MBTL3 against a panel of methyllysine reader proteins, particularly the related MBT family proteins, L3MBTL1 and MBTD1. A co-crystal structure of L3MBTL3 and one of the most potent compounds suggests that the L3MBTL3 dimer rotates about the dimer interface to accommodate ligand binding.