(+)-JQ1   

GtoPdb Ligand ID: 7511

Compound class: Synthetic organic
Comment: JQ1 is a selective and potent inhibitor of BET family bromodomains [2]. This is a compound from the Structural Genomics Consortium's (SGC) Epigenetics Probes Collection.
2D Structure
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Physico-chemical Properties
Hydrogen bond acceptors 5
Hydrogen bond donors 0
Rotatable bonds 5
Topological polar surface area 97.09
Molecular weight 456.14
XLogP 6.41
No. Lipinski's rules broken 1
SMILES / InChI / InChIKey
Canonical SMILES O=C(OC(C)(C)C)CC1N=C(c2ccc(cc2)Cl)c2c(n3c1nnc3C)sc(c2C)C
Isomeric SMILES O=C(OC(C)(C)C)C[C@@H]1N=C(c2ccc(cc2)Cl)c2c(n3c1nnc3C)sc(c2C)C
InChI InChI=1S/C23H25ClN4O2S/c1-12-13(2)31-22-19(12)20(15-7-9-16(24)10-8-15)25-17(11-18(29)30-23(4,5)6)21-27-26-14(3)28(21)22/h7-10,17H,11H2,1-6H3/t17-/m0/s1
InChI Key DNVXATUJJDPFDM-KRWDZBQOSA-N
Bioactivity Comments
JQ1 displaces BRD4 from nuclear chromatin in vitro, induces squamous cell differentiation and growth arrest in NUT midline carcinoma (NMC) cells and exhibits antitumour activity in xenograft models of NMC [2]. (+)-JQ1 binds to BRD4-BD1 with a Kd of approximately 50nM and to BRD4-BD2 with a Kd of 90 nM [2]. In male mice, (+)-JQ1 inhibits the chromatin remodelling that is essential during spermatogenesis, and has a complete and reversible contraceptive effect [3]. Crystallographic study shows that (+)-JQ1 occupies the acetylysine binding site on BRDT, thus preventing BRDT-histone H4 interaction [3].

JQ1-induced inhibition of BET domain containing proteins such as BRD4, inactivates Myc oncogene activity, which in turn switches off expression of programmed death-ligand 1 (PD-L1) and CD47 [1]. Both PD-L1 and CD47 are up-regulated in tumours under Myc control and act in concert to suppress immune detection of the cancer cells. Thus, Myc inhibition appears as a novel immuno-oncology target.
Selectivity at enzymes
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Target Sp. Type Action Value Parameter Concentration range (M) Reference
bromodomain containing 4 Hs Inhibitor Inhibition 7.3 pKd - 2
pKd 7.3 (Kd 5x10-8 M) [2]
Description: Displacement binding constant to recombinant BRD4-BD1 protein.
Selectivity at other protein targets
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Target Sp. Type Action Value Parameter Concentration range (M) Reference
bromodomain testis associated Mm Inhibitor Inhibition 8.0 pIC50 - 3
pIC50 8.0 (IC50 1x10-8 M) [3]
Description: Inhibition of H4Kac4 binding to mBRDT-BD1
bromodomain testis associated Hs Inhibitor Inhibition 8.0 pIC50 - 3
pIC50 8.0 (IC50 1.1x10-8 M) [3]
Description: Inhibition of H4Kac4 binding to hBRDT-BD1