__smbhome.uscs.susx.ac.uk_tjk30_Documents_Final paper after reviewers.pdf (878.14 kB)
Synthesis and biological investigation of (+)-JD1, an organometallic BET bromodomain inhibitor
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
OrganometallicsISSN
0276-7333Publisher
American Chemical SocietyExternal DOI
Department affiliated with
- Biochemistry Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2019-12-19First Open Access (FOA) Date
2020-12-18First Compliant Deposit (FCD) Date
2019-12-18Usage metrics
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