TY - JOUR
T1 - Structure-Guided Design of IACS-9571, a Selective High-Affinity Dual TRIM24-BRPF1 Bromodomain Inhibitor
AU - Palmer, Wylie S.
AU - Poncet-Montange, Guillaume
AU - Liu, Gang
AU - Petrocchi, Alessia
AU - Reyna, Naphtali
AU - Subramanian, Govindan
AU - Theroff, Jay
AU - Yau, Anne
AU - Kost-Alimova, Maria
AU - Bardenhagen, Jennifer P.
AU - Leo, Elisabetta
AU - Shepard, Hannah E.
AU - Tieu, Trang N.
AU - Shi, Xi
AU - Zhan, Yanai
AU - Zhao, Shuping
AU - Barton, Michelle C.
AU - Draetta, Giulio
AU - Toniatti, Carlo
AU - Jones, Philip
AU - Geck Do, Mary
AU - Andersen, Jannik N.
N1 - Funding Information:
We thank Gilbert Lee IV at the CBSF (Core for Biomolecular Structure and Function) for providing BRPF1 purified protein. The authors also thank James Holton and George Meigs for technical help at the Advance Light Source synchrotron facility at the Lawrence Berkeley National Laboratory. We thank Eun Jeong Cho and Kevin N. Dalby at the University of Texas at Austin and the TxSACT (Texas Screening Alliance for Cancer Therapeutics) program for performing the TRIM24 HTS screen. The TxSACT-New Drug Discovery program is supported by CPRIT (Cancer Prevention Research Institute of Texas) Grant RP110532. We thank Stefan Knapp at the Structural Genomics Consortium for providing the template for Figure 4, and Richard Lewis for feedback and proofreading of the manuscript.
Publisher Copyright:
© 2015 American Chemical Society.
PY - 2016/2/25
Y1 - 2016/2/25
N2 - The bromodomain containing proteins TRIM24 (tripartite motif containing protein 24) and BRPF1 (bromodomain and PHD finger containing protein 1) are involved in the epigenetic regulation of gene expression and have been implicated in human cancer. Overexpression of TRIM24 correlates with poor patient prognosis, and BRPF1 is a scaffolding protein required for the assembly of histone acetyltransferase complexes, where the gene of MOZ (monocytic leukemia zinc finger protein) was first identified as a recurrent fusion partner in leukemia patients (8p11 chromosomal rearrangements). Here, we present the structure guided development of a series of N,N-dimethylbenzimidazolone bromodomain inhibitors through the iterative use of X-ray cocrystal structures. A unique binding mode enabled the design of a potent and selective inhibitor 8i (IACS-9571) with low nanomolar affinities for TRIM24 and BRPF1 (ITC Kd = 31 nM and ITC Kd = 14 nM, respectively). With its excellent cellular potency (EC50 = 50 nM) and favorable pharmacokinetic properties (F = 29%), 8i is a high-quality chemical probe for the evaluation of TRIM24 and/or BRPF1 bromodomain function in vitro and in vivo.
AB - The bromodomain containing proteins TRIM24 (tripartite motif containing protein 24) and BRPF1 (bromodomain and PHD finger containing protein 1) are involved in the epigenetic regulation of gene expression and have been implicated in human cancer. Overexpression of TRIM24 correlates with poor patient prognosis, and BRPF1 is a scaffolding protein required for the assembly of histone acetyltransferase complexes, where the gene of MOZ (monocytic leukemia zinc finger protein) was first identified as a recurrent fusion partner in leukemia patients (8p11 chromosomal rearrangements). Here, we present the structure guided development of a series of N,N-dimethylbenzimidazolone bromodomain inhibitors through the iterative use of X-ray cocrystal structures. A unique binding mode enabled the design of a potent and selective inhibitor 8i (IACS-9571) with low nanomolar affinities for TRIM24 and BRPF1 (ITC Kd = 31 nM and ITC Kd = 14 nM, respectively). With its excellent cellular potency (EC50 = 50 nM) and favorable pharmacokinetic properties (F = 29%), 8i is a high-quality chemical probe for the evaluation of TRIM24 and/or BRPF1 bromodomain function in vitro and in vivo.
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U2 - 10.1021/acs.jmedchem.5b00405
DO - 10.1021/acs.jmedchem.5b00405
M3 - Article
C2 - 26061247
AN - SCOPUS:84959366723
SN - 0022-2623
VL - 59
SP - 1440
EP - 1454
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 4
ER -