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; Chevassut, Timothy; Walker, Martin; Austin, Carol; Morley, Simon; Spencer, John

Synthesis and biological investigation of (+)-JD1, an organometallic BET bromodomain inhibitor

https://hdl.handle.net/10779/uos.23474111

journal contribution

posted on 2023-06-09, 20:00 authored by Storm Hassell-HartStorm 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 Stewart, Timothy ChevassutTimothy Chevassut, Martin Walker, Carol Austin, Simon Morley, John SpencerJohn Spencer

(+)-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.

Funding

Drug-induced selective lethality in populations of DNMT3A knockdown cells; G2782; WELLCOME TRUST; 218435/Z/19/Z

Mining the Wnt signalling-responsive surfaceome for drug targets in acute myeloid leukaemia; G3090; WELLCOME TRUST

Poised Fragment Libraries for Atypical Bromodomain Inhibition; G2210; EPSRC-ENGINEERING & PHYSICAL SCIENCES RESEARCH COUNCIL; EP/P026990/1

In vitro modelling and therapeutic targeting of tumour cell migration in chronic lymphocytic leukaemia.; G2544; BLOODWISE

How does SARS CoV-2 infect blood vessels?; G3146; UK RESEARCH AND INNOVATION; MR/V036750/1

Modelling and targeting Acute Myeloid Leukaemia cells in the Bone Marrow protective niche; G3106; SUSSEX CANCER FUND FOR TREATMENT AND RESEARCH

History

Publication status

Published

File Version

Accepted version

Journal

Organometallics

ISSN

0276-7333

Publisher

American Chemical Society

External DOI

https://doi.org/10.1021/acs.organomet.9b00750

Department affiliated with

Biochemistry Publications

Full text available

Yes

Peer reviewed?

Yes

Legacy Posted Date

2019-12-19

First Open Access (FOA) Date

2020-12-18

First Compliant Deposit (FCD) Date

2019-12-18

Synthesis and biological investigation of (+)-JD1, an organometallic BET bromodomain inhibitor

Funding

Drug-induced selective lethality in populations of DNMT3A knockdown cells; G2782; WELLCOME TRUST; 218435/Z/19/Z

Mining the Wnt signalling-responsive surfaceome for drug targets in acute myeloid leukaemia; G3090; WELLCOME TRUST

Poised Fragment Libraries for Atypical Bromodomain Inhibition; G2210; EPSRC-ENGINEERING & PHYSICAL SCIENCES RESEARCH COUNCIL; EP/P026990/1

In vitro modelling and therapeutic targeting of tumour cell migration in chronic lymphocytic leukaemia.; G2544; BLOODWISE

How does SARS CoV-2 infect blood vessels?; G3146; UK RESEARCH AND INNOVATION; MR/V036750/1

Modelling and targeting Acute Myeloid Leukaemia cells in the Bone Marrow protective niche; G3106; SUSSEX CANCER FUND FOR TREATMENT AND RESEARCH

History

Publication status

File Version

Journal

ISSN

Publisher

External DOI

Department affiliated with

Full text available

Peer reviewed?

Legacy Posted Date

First Open Access (FOA) Date

First Compliant Deposit (FCD) Date

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