Rapid Elaboration of Fragments into Leads Applied to Bromodomain-3 Extra-Terminal Domain

被引：2

作者：

Adams, Luke A. ^{[2
]}

Wilkinson-White, Lorna E. ^{[1
]}

Gunzburg, Menachem J. ^{[2
]}

Headey, Stephen J. ^{[2
,3
]}

Mohanty, Biswaranjan ^{[1
]}

Scanlon, Martin J. ^{[2
]}

Capuano, Ben ^{[2
]}

Mackay, Joel P. ^{[4
]}

Doak, Bradley C. ^{[2
]}

机构：

[1] Univ Sydney, Sydney Analyt Core Res Facil, Camperdown, NSW 2006, Australia

[2] Monash Univ, Monash Inst Pharmaceut Sci, Med Chem, Parkville, VIC 3052, Australia

[3] RMIT Univ, Sch Sci, GPO Box 2476, Melbourne, Vic 3001, Australia

[4] Univ Sydney, Sch Life & Environm Sci, Camperdown, NSW 2006, Australia

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2023年 / 66卷 / 08期

基金：

澳大利亚国家健康与医学研究理事会;

关键词：

DRUG DISCOVERY; INHIBITORS; MECHANISM; IDENTIFICATION; BINDING; DESIGN; MOTIF;

D O I：

10.1021/acs.jmedchem.3c00137

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The development of low-affinity fragment hits into higher-affinity leads is a major hurdle in fragment-based drug design. Here, we demonstrate the Rapid Elaboration of Fragments into Leads (REFiL) by applying an integrated workflow that provides a systematic approach to generate higher-affinity binders without the need for structural information. The workflow involves the selection of commercial analogues of fragment hits to generate preliminary structure-activity relationships. This is followed by parallel microscale chemistry using chemoinformatically designed reagent libraries to rapidly explore chemical diversity. After a fragment screen against bromodomain-3 extra-terminal (BRD3ET) domain, we applied the REFiL workflow, which allowed us to develop a series of ligands that bind to BRD3-ET. With REFiL, we were able to rapidly improve binding affinity > 30-fold. REFiL can be applied readily to a broad range of proteins without the need for a structure, allowing the efficient evolution of low-affinity fragments into higher-affinity leads and chemical probes.

引用

页码：5859 / 5872

页数：14

共 39 条

[11] Bromodomains: a new target class for drug development [J].

Cochran, Andrea G. ;

Conery, Andrew R. ;

Sims, Robert J., III .

NATURE REVIEWS DRUG DISCOVERY, 2019, 18 (08) :609-628

[12] Structure of the Brd4 ET domain bound to a C-terminal motif from γ-retroviral integrases reveals a conserved mechanism of interaction [J].

Crowe, Brandon L. ;

Larue, Ross C. ;

Yuan, Chunhua ;

Hess, Sonja ;

Kvaratskhelia, Mamuka ;

Foster, Mark P. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2016, 113 (08) :2086-2091

[13] Direct comparison of binding equilibrium, thermodynamic, and rate constants determined by surface- and solution-based biophysical methods [J].

Day, YSN ;

Baird, CL ;

Rich, RL ;

Myszka, DG .

PROTEIN SCIENCE, 2002, 11 (05) :1017-1025

[14] Twenty years on: the impact of fragments on drug discovery [J].

Erlanson, Daniel A. ;

Fesik, Stephen W. ;

Hubbard, Roderick E. ;

Jahnke, Wolfgang ;

Jhoti, Harren .

NATURE REVIEWS DRUG DISCOVERY, 2016, 15 (09) :605-619

[15] How Are Fragments Optimized? A Retrospective Analysis of 145 Fragment Optimizations [J].

Ferenczy, Gyoergy G. ;

Keseru, Gyoergy M. .

JOURNAL OF MEDICINAL CHEMISTRY, 2013, 56 (06) :2478-2486

[16] Nanoscale, automated, high throughput synthesis and screening for the accelerated discovery of protein modifiers [J].

Gao, Kai ;

Shaabani, Shabnam ;

Xu, Ruixue ;

Zarganes-Tzitzikas, Tryfon ;

Gao, Li ;

Ahmadianmoghaddam, Maryam ;

Groves, Matthew R. ;

Domling, Alexander .

RSC MEDICINAL CHEMISTRY, 2021, 12 (05) :809-818

[17] Nanoscale synthesis and affinity ranking [J].

Gesmundo, Nathan J. ;

Sauvagnat, Berengere ;

Curran, Patrick J. ;

Richards, Matthew P. ;

Andrews, Christine L. ;

Dandliker, Peter J. ;

Cernak, Tim .

NATURE, 2018, 557 (7704) :228-+

[18] FROM EXPERIMENTAL DESIGN TO VALIDATED HITS: A COMPREHENSIVE WALK-THROUGH OF FRAGMENT LEAD IDENTIFICATION USING SURFACE PLASMON RESONANCE [J].

Giannetti, Anthony M. .

FRAGMENT-BASED DRUG DESIGN: TOOLS, PRACTICAL APPROACHES, AND EXAMPLES, 2011, 493 :169-218

[19] Activity-Directed Synthesis of Inhibitors of the p53/hDM2 Protein-Protein Interaction [J].

Green, Adam I. ;

Hobor, Fruzsina ;

Tinworth, Christopher P. ;

Warriner, Stuart ;

Wilson, Andrew J. ;

Nelson, Adam .

CHEMISTRY-A EUROPEAN JOURNAL, 2020, 26 (47) :10682-10689

[20] Synthesis and direct assay of large macrocycle diversities by combinatorial late-stage modification at picomole scale [J].

Habeshian, Sevan ;

Merz, Manuel Leonardo ;

Sangouard, Gontran ;

Mothukuri, Ganesh Kumar ;

Schuettel, Mischa ;

Bognar, Zsolt ;

Diaz-Perlas, Cristina ;

Vesin, Jonathan ;

Chapalay, Julien Bortoli ;

Turcatti, Gerardo ;

Cendron, Laura ;

Angelini, Alessandro ;

Heinis, Christian .

NATURE COMMUNICATIONS, 2022, 13 (01)

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