The structure-activity relationships of L3MBTL3 inhibitors: flexibility of the dimer interface.
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.
Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, University of North Carolina Eshelman School of Pharmacy University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. ; Tel: (919) 843-5486.
Michelle A
MA
Camerino
Structural Genomics Consortium, University of Toronto, Ontario, Canada.
Nan
N
Zhong
Structural Genomics Consortium, University of Toronto, Ontario, Canada.
Aiping
A
Dong
Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, University of North Carolina Eshelman School of Pharmacy University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. ; Tel: (919) 843-5486.
Bradley M
BM
Dickson
Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, University of North Carolina Eshelman School of Pharmacy University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. ; Tel: (919) 843-5486.
Lindsey I
LI
James
Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, University of North Carolina Eshelman School of Pharmacy University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. ; Tel: (919) 843-5486.
Brandi M
BM
Baughman
Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, University of North Carolina Eshelman School of Pharmacy University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. ; Tel: (919) 843-5486.
Jacqueline L
JL
Norris
Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, University of North Carolina Eshelman School of Pharmacy University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. ; Tel: (919) 843-5486.
Dmitri B
DB
Kireev
Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, University of North Carolina Eshelman School of Pharmacy University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. ; Tel: (919) 843-5486.
William P
WP
Janzen
Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, University of North Carolina Eshelman School of Pharmacy University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. ; Tel: (919) 843-5486 ; Structural Genomics Consortium, University of Toronto, Ontario, Canada ; Department of Medical Biophysics, University of Toronto Ontario, Canada ; Princess Margaret Cancer Centre, 101 College Street, Toronto, Ontario, Canada, M5G 1L7.
Cheryl H
CH
Arrowsmith
Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, University of North Carolina Eshelman School of Pharmacy University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. ; Tel: (919) 843-5486.
Stephen V
SV
Frye