Optimization of Phenyl Indole Inhibitors of the AAA+ ATPase p97

被引：16

作者：

LaPorte, Matthew G. ^{[1
]}

Burnett, James C. ^{[1
,2
]}

Colombo, Raffaele ^{[1
]}

Bulfer, Stacie L. ^{[3
]}

Alverez, Celeste ^{[1
,4
]}

Chou, Tsui-Fen ^{[5
,6
]}

Neitz, R. Jeffrey ^{[3
]}

Green, Neal ^{[7
]}

Moore, William J. ^{[7
]}

Yue, Zhizhou ^{[1
]}

Li, Shan ^{[5
,6
]}

Arkin, Michelle R. ^{[3
]}

Wipf, Peter ^{[1
,4
]}

Huryn, Donna M. ^{[1
,4
]}

机构：

[1] Univ Pittsburgh, Chem Divers Ctr, Pittsburgh, PA 15260 USA

[2] NCI, Computat Drug Dev Grp, Dev Therapeut Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA

[3] Univ Calif San Francisco, Dept Pharmaceut Chem, Small Mol Discovery Ctr, San Francisco, CA 94158 USA

[4] Univ Pittsburgh, Dept Pharmaceut Sci, Pittsburgh, PA 15260 USA

[5] Harbor UCLA Med Ctr, Div Med Genet, Dept Pediat, Torrance, CA 90502 USA

[6] Los Angeles Biomed Res Inst, Torrance, CA 90502 USA

[7] Leidos Biomed Res Inc, Frederick, MD 21702 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2018年 / 9卷 / 11期

基金：

美国国家卫生研究院;

关键词：

AAA plus ATPase; p97; allosteric inhibitor; protein homeostasis modulator; anticancer; phenyl indole; CHAPERONE P97; UBIQUITIN; MECHANISM; CANCER; POTENT;

D O I：

10.1021/acsmedchemlett.8b00372

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Optimization of the side-chain of a phenyl indole scaffold identified from a high-throughput screening campaign for inhibitors of the AAA+ ATPase p97 is reported. The addition of an N-alkyl piperazine led to high potency of this series in a biochemical assay, activity in cell-based assays, and excellent pharmaceutical properties. Molecular modeling based on a subsequently obtained cryo-EM structure of p97 in complex with a phenyl indole was used to rationalize the potency of these allosteric inhibitors.

引用

页码：1075 / 1081

页数：13

共 50 条

[1] 2-Phenyl indole piperazine inhibitors of AAA ATPase p97
Chatterley, Alexander
Miller, Eric
Alverez, Celeste
Kovaliov, Marina
Lim, Chaemin
Colombo, Raffaele
Yue, Zhizhou
LaPorte, Matt
Samankumura, Lalith
Bulfer, Stacie
Arkin, Michelle
Huryn, Donna
Wipf, Peter
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2016, 252
[2] Inhibitors of the AAA+ Chaperone p97
Chapman, Eli
Maksim, Nick
de la Cruz, Fabian
La Clair, James J.
MOLECULES, 2015, 20 (02): : 3027 - 3049
[3] The AAA+ ATPase p97, a cellular multitool
Stach, Lasse
Freemont, Paul S.
BIOCHEMICAL JOURNAL, 2017, 474 : 2953 - 2976
[4] Development of p97 AAA ATPase inhibitors
Chou, Tsui-Fen
Deshaies, Raymond J.
AUTOPHAGY, 2011, 7 (09) : 1091 - 1092
[5] The AAA+ ATPase p97 as a novel parasite and tuberculosis drug target
Kobakhidze, George
Sethi, Ashish
Valimehr, Sepideh
Ralph, Stuart A.
Rouiller, Isabelle
TRENDS IN PARASITOLOGY, 2022, 38 (07) : 572 - 590
[6] Remodeling of the AAA+ ATPase p97 by the UBX Adaptor Protein ASPL
Heinemann, U.
Roske, Y.
Arumughan, A.
Wanker, E.
ACTA CRYSTALLOGRAPHICA A-FOUNDATION AND ADVANCES, 2014, 70 : C430 - C430
[7] Nucleotide-dependent conformational changes of the AAA+ ATPase p97 revisited
Schuller, Jan M.
Beck, Florian
Lossl, Philip
Heck, Albert J. R.
Foerster, Friedrich
FEBS LETTERS, 2016, 590 (05) : 595 - 604
[8] Single-Molecule and Ensemble Structural Study of the AAA+ Atpase P97
Lee, Taehyung
Kang, MinJin
Chapman, Eli
Deniz, Ashok A.
BIOPHYSICAL JOURNAL, 2014, 106 (02) : 49A - 49A
[9] Structural Basis of ATP Hydrolysis and Intersubunit Signaling in the AAA+ ATPase p97
Haenzelmann, Petra
Schindelin, Hermann
STRUCTURE, 2016, 24 (01) : 127 - 139
[10] Modular synthesis of allosteric inhibitors of p97 AAA ATPase
Carder, Evan
Huryn, Donna
Wipf, Peter
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2018, 256

← 1 2 3 4 5 →