Design of a Biased Potent Small Molecule Inhibitor of the Bromodomain and PHD Finger-Containing (BRPF) Proteins Suitable for Cellular and in Vivo Studies

Niall Igoe; Elliott D Bayle; Oleg Fedorov; Cynthia Tallant; Pavel Savitsky; Catherine Rogers; Dafydd R Owen; Gauri Deb; Tim C P Somervaille; David M Andrews; Neil Jones; Anne Cheasty; Hamish Ryder; Paul E Brennan; Susanne Müller; Stefan Knapp; Paul V Fish

doi:10.1021/acs.jmedchem.6b01583

Design of a Biased Potent Small Molecule Inhibitor of the Bromodomain and PHD Finger-Containing (BRPF) Proteins Suitable for Cellular and in Vivo Studies

Niall Igoe
, Elliott D Bayle
, Oleg Fedorov
, Cynthia Tallant
, Pavel Savitsky
, Catherine Rogers
, Dafydd R Owen
, Gauri Deb
, Tim C P Somervaille
, David M Andrews
, Neil Jones
, Anne Cheasty
, Hamish Ryder
, Paul E Brennan
, Susanne Müller
, Stefan Knapp
, Paul V Fish

Cancer Research UK Manchester Institute

Research output: Contribution to journal › Article › peer-review

Abstract

The BRPF (bromodomain and PHD finger-containing) family are scaffolding proteins important for the recruitment of histone acetyltransferases of the MYST family to chromatin. Evaluation of the BRPF family as a potential drug target is at an early stage although there is an emerging understanding of a role in acute myeloid leukemia (AML). We report the optimization of fragment hit 5b to 13-d as a biased, potent inhibitor of the BRD of the BRPFs with excellent selectivity over nonclass IV BRD proteins. Evaluation of 13-d in a panel of cancer cell lines showed a selective inhibition of proliferation of a subset of AML lines. Pharmacokinetic studies established that 13-d had properties compatible with oral dosing in mouse models of disease (F_po 49%). We propose that NI-42 (13-d) is a new chemical probe for the BRPFs suitable for cellular and in vivo studies to explore the fundamental biology of these proteins.

Original language	English
Pages (from-to)	668-680
Number of pages	13
Journal	Journal of Medicinal Chemistry
Volume	60
Issue number	2
Early online date	9 Jan 2017
DOIs	https://doi.org/10.1021/acs.jmedchem.6b01583
Publication status	Published - 26 Jan 2017

Keywords

Adaptor Proteins, Signal Transducing/antagonists & inhibitors
Animals
Antineoplastic Agents/chemical synthesis
Cell Line, Tumor
DNA-Binding Proteins
Drug Screening Assays, Antitumor
Humans
Leukemia, Myeloid, Acute/drug therapy
Mice
Microsomes, Liver/metabolism
Nuclear Proteins/antagonists & inhibitors
Protein Domains
Quinolones/chemical synthesis
Structure-Activity Relationship
Sulfonamides/chemical synthesis

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1021/acs.jmedchem.6b01583

Cite this

Igoe, N., Bayle, E. D., Fedorov, O., Tallant, C., Savitsky, P., Rogers, C., Owen, D. R., Deb, G., Somervaille, T. C. P., Andrews, D. M., Jones, N., Cheasty, A., Ryder, H., Brennan, P. E., Müller, S., Knapp, S., & Fish, P. V. (2017). Design of a Biased Potent Small Molecule Inhibitor of the Bromodomain and PHD Finger-Containing (BRPF) Proteins Suitable for Cellular and in Vivo Studies. Journal of Medicinal Chemistry, 60(2), 668-680. https://doi.org/10.1021/acs.jmedchem.6b01583

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title = "Design of a Biased Potent Small Molecule Inhibitor of the Bromodomain and PHD Finger-Containing (BRPF) Proteins Suitable for Cellular and in Vivo Studies",

abstract = "The BRPF (bromodomain and PHD finger-containing) family are scaffolding proteins important for the recruitment of histone acetyltransferases of the MYST family to chromatin. Evaluation of the BRPF family as a potential drug target is at an early stage although there is an emerging understanding of a role in acute myeloid leukemia (AML). We report the optimization of fragment hit 5b to 13-d as a biased, potent inhibitor of the BRD of the BRPFs with excellent selectivity over nonclass IV BRD proteins. Evaluation of 13-d in a panel of cancer cell lines showed a selective inhibition of proliferation of a subset of AML lines. Pharmacokinetic studies established that 13-d had properties compatible with oral dosing in mouse models of disease (Fpo 49\%). We propose that NI-42 (13-d) is a new chemical probe for the BRPFs suitable for cellular and in vivo studies to explore the fundamental biology of these proteins.",

keywords = "Adaptor Proteins, Signal Transducing/antagonists \& inhibitors, Animals, Antineoplastic Agents/chemical synthesis, Cell Line, Tumor, DNA-Binding Proteins, Drug Screening Assays, Antitumor, Humans, Leukemia, Myeloid, Acute/drug therapy, Mice, Microsomes, Liver/metabolism, Nuclear Proteins/antagonists \& inhibitors, Protein Domains, Quinolones/chemical synthesis, Structure-Activity Relationship, Sulfonamides/chemical synthesis",

author = "Niall Igoe and Bayle, \{Elliott D\} and Oleg Fedorov and Cynthia Tallant and Pavel Savitsky and Catherine Rogers and Owen, \{Dafydd R\} and Gauri Deb and Somervaille, \{Tim C P\} and Andrews, \{David M\} and Neil Jones and Anne Cheasty and Hamish Ryder and Brennan, \{Paul E\} and Susanne M{\"u}ller and Stefan Knapp and Fish, \{Paul V\}",

year = "2017",

month = jan,

day = "26",

doi = "10.1021/acs.jmedchem.6b01583",

language = "English",

volume = "60",

pages = "668--680",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "2",

}

Igoe, N, Bayle, ED, Fedorov, O, Tallant, C, Savitsky, P, Rogers, C, Owen, DR, Deb, G, Somervaille, TCP, Andrews, DM, Jones, N, Cheasty, A, Ryder, H, Brennan, PE, Müller, S, Knapp, S & Fish, PV 2017, 'Design of a Biased Potent Small Molecule Inhibitor of the Bromodomain and PHD Finger-Containing (BRPF) Proteins Suitable for Cellular and in Vivo Studies', Journal of Medicinal Chemistry, vol. 60, no. 2, pp. 668-680. https://doi.org/10.1021/acs.jmedchem.6b01583

TY - JOUR

T1 - Design of a Biased Potent Small Molecule Inhibitor of the Bromodomain and PHD Finger-Containing (BRPF) Proteins Suitable for Cellular and in Vivo Studies

AU - Igoe, Niall

AU - Bayle, Elliott D

AU - Fedorov, Oleg

AU - Tallant, Cynthia

AU - Savitsky, Pavel

AU - Rogers, Catherine

AU - Owen, Dafydd R

AU - Deb, Gauri

AU - Somervaille, Tim C P

AU - Andrews, David M

AU - Jones, Neil

AU - Cheasty, Anne

AU - Ryder, Hamish

AU - Brennan, Paul E

AU - Müller, Susanne

AU - Knapp, Stefan

AU - Fish, Paul V

PY - 2017/1/26

Y1 - 2017/1/26

N2 - The BRPF (bromodomain and PHD finger-containing) family are scaffolding proteins important for the recruitment of histone acetyltransferases of the MYST family to chromatin. Evaluation of the BRPF family as a potential drug target is at an early stage although there is an emerging understanding of a role in acute myeloid leukemia (AML). We report the optimization of fragment hit 5b to 13-d as a biased, potent inhibitor of the BRD of the BRPFs with excellent selectivity over nonclass IV BRD proteins. Evaluation of 13-d in a panel of cancer cell lines showed a selective inhibition of proliferation of a subset of AML lines. Pharmacokinetic studies established that 13-d had properties compatible with oral dosing in mouse models of disease (Fpo 49%). We propose that NI-42 (13-d) is a new chemical probe for the BRPFs suitable for cellular and in vivo studies to explore the fundamental biology of these proteins.

AB - The BRPF (bromodomain and PHD finger-containing) family are scaffolding proteins important for the recruitment of histone acetyltransferases of the MYST family to chromatin. Evaluation of the BRPF family as a potential drug target is at an early stage although there is an emerging understanding of a role in acute myeloid leukemia (AML). We report the optimization of fragment hit 5b to 13-d as a biased, potent inhibitor of the BRD of the BRPFs with excellent selectivity over nonclass IV BRD proteins. Evaluation of 13-d in a panel of cancer cell lines showed a selective inhibition of proliferation of a subset of AML lines. Pharmacokinetic studies established that 13-d had properties compatible with oral dosing in mouse models of disease (Fpo 49%). We propose that NI-42 (13-d) is a new chemical probe for the BRPFs suitable for cellular and in vivo studies to explore the fundamental biology of these proteins.

KW - Adaptor Proteins, Signal Transducing/antagonists & inhibitors

KW - Animals

KW - Antineoplastic Agents/chemical synthesis

KW - Cell Line, Tumor

KW - DNA-Binding Proteins

KW - Drug Screening Assays, Antitumor

KW - Humans

KW - Leukemia, Myeloid, Acute/drug therapy

KW - Mice

KW - Microsomes, Liver/metabolism

KW - Nuclear Proteins/antagonists & inhibitors

KW - Protein Domains

KW - Quinolones/chemical synthesis

KW - Structure-Activity Relationship

KW - Sulfonamides/chemical synthesis

U2 - 10.1021/acs.jmedchem.6b01583

DO - 10.1021/acs.jmedchem.6b01583

M3 - Article

C2 - 28068087

SN - 0022-2623

VL - 60

SP - 668

EP - 680

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 2

ER -

Design of a Biased Potent Small Molecule Inhibitor of the Bromodomain and PHD Finger-Containing (BRPF) Proteins Suitable for Cellular and in Vivo Studies

Abstract

Keywords

UN SDGs

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