Discovery of a Potent and Selective in Vivo Probe (GNE-272) for the Bromodomains of CBP/EP300.
The single bromodomain of the closely related transcriptional regulators CBP/EP300 is a target of much recent interest in cancer and immune system regulation. A co-crystal structure of a ligand-efficient screening hit and the CBP bromodomain guided initial design targeting the LPF shelf, ZA loop, and acetylated lysine binding regions. Structure-activity relationship studies allowed us to identify a more potent analogue. Optimization of permeability and microsomal stability and subsequent improvement of mouse hepatocyte stability afforded 59 (GNE-272, TR-FRET IC50= 0.02 μM, BRET IC50= 0.41 μM, BRD4(1) IC50= 13 μM) that retained the best balance of cell potency, selectivity, and in vivo PK. Compound 59 showed a marked antiproliferative effect in hematologic cancer cell lines and modulates MYC expression in vivo that corresponds with antitumor activity in an AML tumor model.
Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States.
Terry D
TD
Crawford
Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States.
F Anthony
FA
Romero
Wuxi Apptec Co., Ltd. , 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, People's Republic of China.
Kwong Wah
KW
Lai
Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States.
Vickie
V
Tsui
Constellation Pharmaceuticals, Inc. 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
Alexander M
AM
Taylor
Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States.
Gladys
G
de Leon Boenig
Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States.
Cameron L
CL
Noland
Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States.
Jeremy
J
Murray
Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States.
Justin
J
Ly
Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States.
Edna F
EF
Choo
Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States.
Thomas L
TL
Hunsaker
Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States.
Emily W
EW
Chan
Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States.
Mark
M
Merchant
Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States.
Samir
S
Kharbanda
Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States.
Karen E
KE
Gascoigne
Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States.
Susan
S
Kaufman
Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States.
Maureen H
MH
Beresini
Wuxi Apptec Co., Ltd. , 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, People's Republic of China.
Jiangpeng
J
Liao
Wuxi Apptec Co., Ltd. , 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, People's Republic of China.
Wenfeng
W
Liu
Wuxi Apptec Co., Ltd. , 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, People's Republic of China.
Kevin X
KX
Chen
Wuxi Apptec Co., Ltd. , 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, People's Republic of China.
Zhongguo
Z
Chen
Constellation Pharmaceuticals, Inc. 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
Andrew R
AR
Conery
Constellation Pharmaceuticals, Inc. 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
Alexandre
A
Côté
Constellation Pharmaceuticals, Inc. 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
Hariharan
H
Jayaram
Wuxi Apptec Co., Ltd. , 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, People's Republic of China.
Ying
Y
Jiang
Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States.
James R
JR
Kiefer
Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States.
Tracy
T
Kleinheinz
Wuxi Apptec Co., Ltd. , 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, People's Republic of China.
Yingjie
Y
Li
Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States.
Jonathan
J
Maher
Constellation Pharmaceuticals, Inc. 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
Eneida
E
Pardo
Constellation Pharmaceuticals, Inc. 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
Florence
F
Poy
Constellation Pharmaceuticals, Inc. 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
Kerry L
KL
Spillane
Wuxi Apptec Co., Ltd. , 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, People's Republic of China.
Fei
F
Wang
Wuxi Apptec Co., Ltd. , 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, People's Republic of China.
Jian
J
Wang
Wuxi Apptec Co., Ltd. , 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, People's Republic of China.
Xiaocang
X
Wei
Wuxi Apptec Co., Ltd. , 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, People's Republic of China.
Zhaowu
Z
Xu
Wuxi Apptec Co., Ltd. , 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, People's Republic of China.
Zhongya
Z
Xu
Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States.
Ivana
I
Yen
Constellation Pharmaceuticals, Inc. 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
Laura
L
Zawadzke
Wuxi Apptec Co., Ltd. , 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, People's Republic of China.
Xiaoyu
X
Zhu
Constellation Pharmaceuticals, Inc. 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
Steven
S
Bellon
Constellation Pharmaceuticals, Inc. 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
Richard
R
Cummings
Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States.
Andrea G
AG
Cochran
Constellation Pharmaceuticals, Inc. 215 First Street, Suite 200, Cambridge, Massachusetts 02142, United States.
Brian K
BK
Albrecht
Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, United States.
Steven
S
Magnuson
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D050880:p300-CBP Transcription Factors / Q000037:antagonists & inhibitors*
C000620287:(S)-1-(3-((2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-1-(tetrahydrofuran-3-yl)-6,7-dihydro-1H-pyrazolo(4,3-c)pyridin-5(4H)-yl)ethanone; D000970:Antineoplastic Agents; D011720:Pyrazoles; D011728:Pyridones; D050880:p300-CBP Transcription Factors