Synthesis and Biological Investigation of (+)-JD1, an Organometallic BET Bromodomain Inhibitor

Storm Hassell-Hart; Andrew Runcie; Tobias Krojer; Jordan Doyle; Ella Lineham; Cory A. Ocasio; Brenno A. D. Neto; Oleg Fedorov; Graham Marsh; Hannah Maple; Robert Felix; Rebecca Banks; Alessio Ciulli; Sarah Picaud; Panagis Filippakopoulos; Frank Von Delft; Paul Brennan; Helen J. S. Stewart; Timothy J. Chevassut; Martin Walker; Carol Austin; Simon Morley; John Spencer

doi:10.1021/acs.organomet.9b00750

Synthesis and Biological Investigation of (+)-JD1, an Organometallic BET Bromodomain Inhibitor

Storm Hassell-Hart, Andrew Runcie, Tobias Krojer, Jordan Doyle, Ella Lineham, Cory A. Ocasio, Brenno A. D. Neto, Oleg Fedorov, Graham Marsh, Hannah Maple, Robert Felix, Rebecca Banks, Alessio Ciulli, Sarah Picaud, Panagis Filippakopoulos, Frank Von Delft, Paul Brennan, Helen J. S. Stewart, Timothy J. Chevassut, Martin WalkerCarol Austin, Simon Morley, John Spencer

Biological Chemistry and Drug Discovery

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

2 Citations (Scopus)

Abstract

(+)-JD1, a rationally designed ferrocene analogue of the BET bromodomain (BRD) probe molecule (+)-JQ1, has been synthesized and evaluated in biophysical, cell-based assays as well as in pharmacokinetic studies. It displays nanomolar activity against BRD isoforms, and its cocrystal structure was determined in complex with the first bromodomain of BRD4 and compared with that of (+)-JQ1, a known BRD4 small-molecule probe. At 1 μM concentration, (+)-JD1 was able to inhibit c-Myc, a key driver in cancer and an indirect target of BRD4.

Original language	English
Journal	Organometallics
Early online date	17 Dec 2019
DOIs	https://doi.org/10.1021/acs.organomet.9b00750
Publication status	E-pub ahead of print - 17 Dec 2019

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10.1021/acs.organomet.9b00750

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A Systems Approach for the Fragment-based Development of Selective Chemical Probes of Bromodomain Function (joint with University of Oxford)
Ciulli, A.
Biotechnology and Biological Sciences Research Council
8/04/13 → 7/06/15
Project: Research

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Hassell-Hart, S., Runcie, A., Krojer, T., Doyle, J., Lineham, E., Ocasio, C. A., Neto, B. A. D., Fedorov, O., Marsh, G., Maple, H., Felix, R., Banks, R., Ciulli, A., Picaud, S., Filippakopoulos, P., Von Delft, F., Brennan, P., Stewart, H. J. S., Chevassut, T. J., ... Spencer, J. (2019). Synthesis and Biological Investigation of (+)-JD1, an Organometallic BET Bromodomain Inhibitor. Organometallics. https://doi.org/10.1021/acs.organomet.9b00750

Hassell-Hart, Storm ; Runcie, Andrew ; Krojer, Tobias ; Doyle, Jordan ; Lineham, Ella ; Ocasio, Cory A. ; Neto, Brenno A. D. ; Fedorov, Oleg ; Marsh, Graham ; Maple, Hannah ; Felix, Robert ; Banks, Rebecca ; Ciulli, Alessio ; Picaud, Sarah ; Filippakopoulos, Panagis ; Von Delft, Frank ; Brennan, Paul ; Stewart, Helen J. S. ; Chevassut, Timothy J. ; Walker, Martin ; Austin, Carol ; Morley, Simon ; Spencer, John. / Synthesis and Biological Investigation of (+)-JD1, an Organometallic BET Bromodomain Inhibitor. In: Organometallics. 2019.

@article{e975aca3b145463f85ed266474d6464c,

title = "Synthesis and Biological Investigation of (+)-JD1, an Organometallic BET Bromodomain Inhibitor",

abstract = "(+)-JD1, a rationally designed ferrocene analogue of the BET bromodomain (BRD) probe molecule (+)-JQ1, has been synthesized and evaluated in biophysical, cell-based assays as well as in pharmacokinetic studies. It displays nanomolar activity against BRD isoforms, and its cocrystal structure was determined in complex with the first bromodomain of BRD4 and compared with that of (+)-JQ1, a known BRD4 small-molecule probe. At 1 μM concentration, (+)-JD1 was able to inhibit c-Myc, a key driver in cancer and an indirect target of BRD4.",

author = "Storm Hassell-Hart and Andrew Runcie and Tobias Krojer and Jordan Doyle and Ella Lineham and Ocasio, {Cory A.} and Neto, {Brenno A. D.} and Oleg Fedorov and Graham Marsh and Hannah Maple and Robert Felix and Rebecca Banks and Alessio Ciulli and Sarah Picaud and Panagis Filippakopoulos and {Von Delft}, Frank and Paul Brennan and Stewart, {Helen J. S.} and Chevassut, {Timothy J.} and Martin Walker and Carol Austin and Simon Morley and John Spencer",

year = "2019",

month = dec,

day = "17",

doi = "10.1021/acs.organomet.9b00750",

language = "English",

journal = "Organometallics",

issn = "0276-7333",

publisher = "American Chemical Society",

}

Hassell-Hart, S, Runcie, A, Krojer, T, Doyle, J, Lineham, E, Ocasio, CA, Neto, BAD, Fedorov, O, Marsh, G, Maple, H, Felix, R, Banks, R, Ciulli, A, Picaud, S, Filippakopoulos, P, Von Delft, F, Brennan, P, Stewart, HJS, Chevassut, TJ, Walker, M, Austin, C, Morley, S & Spencer, J 2019, 'Synthesis and Biological Investigation of (+)-JD1, an Organometallic BET Bromodomain Inhibitor', Organometallics. https://doi.org/10.1021/acs.organomet.9b00750

Synthesis and Biological Investigation of (+)-JD1, an Organometallic BET Bromodomain Inhibitor. / Hassell-Hart, Storm; Runcie, Andrew; Krojer, Tobias; Doyle, Jordan; Lineham, Ella; Ocasio, Cory A.; Neto, Brenno A. D.; Fedorov, Oleg; Marsh, Graham; Maple, Hannah; Felix, Robert; Banks, Rebecca; Ciulli, Alessio; Picaud, Sarah; Filippakopoulos, Panagis; Von Delft, Frank; Brennan, Paul; Stewart, Helen J. S.; Chevassut, Timothy J.; Walker, Martin; Austin, Carol; Morley, Simon; Spencer, John (Lead / Corresponding author).

In: Organometallics, 17.12.2019.

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

TY - JOUR

T1 - Synthesis and Biological Investigation of (+)-JD1, an Organometallic BET Bromodomain Inhibitor

AU - Hassell-Hart, Storm

AU - Runcie, Andrew

AU - Krojer, Tobias

AU - Doyle, Jordan

AU - Lineham, Ella

AU - Ocasio, Cory A.

AU - Neto, Brenno A. D.

AU - Fedorov, Oleg

AU - Marsh, Graham

AU - Maple, Hannah

AU - Felix, Robert

AU - Banks, Rebecca

AU - Ciulli, Alessio

AU - Picaud, Sarah

AU - Filippakopoulos, Panagis

AU - Von Delft, Frank

AU - Brennan, Paul

AU - Stewart, Helen J. S.

AU - Chevassut, Timothy J.

AU - Walker, Martin

AU - Austin, Carol

AU - Morley, Simon

AU - Spencer, John

PY - 2019/12/17

Y1 - 2019/12/17

N2 - (+)-JD1, a rationally designed ferrocene analogue of the BET bromodomain (BRD) probe molecule (+)-JQ1, has been synthesized and evaluated in biophysical, cell-based assays as well as in pharmacokinetic studies. It displays nanomolar activity against BRD isoforms, and its cocrystal structure was determined in complex with the first bromodomain of BRD4 and compared with that of (+)-JQ1, a known BRD4 small-molecule probe. At 1 μM concentration, (+)-JD1 was able to inhibit c-Myc, a key driver in cancer and an indirect target of BRD4.

AB - (+)-JD1, a rationally designed ferrocene analogue of the BET bromodomain (BRD) probe molecule (+)-JQ1, has been synthesized and evaluated in biophysical, cell-based assays as well as in pharmacokinetic studies. It displays nanomolar activity against BRD isoforms, and its cocrystal structure was determined in complex with the first bromodomain of BRD4 and compared with that of (+)-JQ1, a known BRD4 small-molecule probe. At 1 μM concentration, (+)-JD1 was able to inhibit c-Myc, a key driver in cancer and an indirect target of BRD4.

UR - http://www.scopus.com/inward/record.url?scp=85077004008&partnerID=8YFLogxK

U2 - 10.1021/acs.organomet.9b00750

DO - 10.1021/acs.organomet.9b00750

M3 - Article

AN - SCOPUS:85077004008

JO - Organometallics

JF - Organometallics

SN - 0276-7333

ER -

Synthesis and Biological Investigation of (+)-JD1, an Organometallic BET Bromodomain Inhibitor

Abstract

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A Systems Approach for the Fragment-based Development of Selective Chemical Probes of Bromodomain Function (joint with University of Oxford)

Cite this