bromodomain inhibitor used in clinical trials for treating NUT-midline carcinoma
(NMC, Clinical Trial ID: NCT01587703).
The corresponding study by Filippakopoulos et al. disclosed a similar diazepine,
(+)-JQ1, derived from a 1,2,4 triazolothienodiazepine (Fig. 6) [9]. This compound
was selected from a prior 2009 patent from Mitsubishi Tanabe Pharma Corporation
(WO 2009084693 A1) [65]. Although (+)-JQ1 was not identified as the most
efficacious compound in the patent, it was selected based on expectations for
reduced off-target receptor binding as well as future derivatization. Interestingly,
the more potent compound from the patent contained a 4-hydroxyphenylacetamide
group in place of the tert-butyl ester of (+)-JQ1. This molecule has since been
licensed by Oncoethix (now OTX-015) and as of 2018 had been tested in phase I
and II clinical trials from Merck for treating solid tumors in various cancers.
For chemical probe development, (+)-JQ1 demonstrated high selectivity for BET
bromodomains by thermal shift assays against a panel of 36 bromodomains with the
Fig. 6 Select BET bromodomain inhibitors from the literature including Pan-BET inhibitors [9, 10,
57–59], BRD4-selective inhibitor, Fl-411 [60], BET BD1 selective inhibitors [61, 62], or BET BD2
selective inhibitors [63, 64], BD1 selective inhibitor V, is shown in Fig. 3
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W. C. K. Pomerantz et al.
(NMC, Clinical Trial ID: NCT01587703).
The corresponding study by Filippakopoulos et al. disclosed a similar diazepine,
(+)-JQ1, derived from a 1,2,4 triazolothienodiazepine (Fig. 6) [9]. This compound
was selected from a prior 2009 patent from Mitsubishi Tanabe Pharma Corporation
(WO 2009084693 A1) [65]. Although (+)-JQ1 was not identified as the most
efficacious compound in the patent, it was selected based on expectations for
reduced off-target receptor binding as well as future derivatization. Interestingly,
the more potent compound from the patent contained a 4-hydroxyphenylacetamide
group in place of the tert-butyl ester of (+)-JQ1. This molecule has since been
licensed by Oncoethix (now OTX-015) and as of 2018 had been tested in phase I
and II clinical trials from Merck for treating solid tumors in various cancers.
For chemical probe development, (+)-JQ1 demonstrated high selectivity for BET
bromodomains by thermal shift assays against a panel of 36 bromodomains with the
Fig. 6 Select BET bromodomain inhibitors from the literature including Pan-BET inhibitors [9, 10,
57–59], BRD4-selective inhibitor, Fl-411 [60], BET BD1 selective inhibitors [61, 62], or BET BD2
selective inhibitors [63, 64], BD1 selective inhibitor V, is shown in Fig. 3
302
W. C. K. Pomerantz et al.