The Discovery and Development of a Safe, Practical Synthesis of ABT-869

Kruger, Albert W.; Rozema, Michael J.; Chu-Kung, Alexander; Gandarilla, Jorge; Haight, Anthony R.; Kotecki, Brian J.; Richter, Steven M.; Schwartz, Albert M.; Wang, Zhe

doi:10.1021/op900208y

Cited by 28 publications

(29 citation statements)

References 17 publications

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“…We evaluated the binding affinities of 28 to the family of BET proteins and its selectivity over bromodomain-containing proteins in the BROMOscan assays by DiscoverX, 26 and the results are summarized in Table 6. The data showed that 28 binds to both the BD1 and BD2 domains of BRD2, BRD3, BRD4, and BRDT BET proteins with high affinities (K d = 0.49−2.2 nM).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Structure-Based Discovery of CF53 as a Potent and Orally Bioavailable Bromodomain and Extra-Terminal (BET) Bromodomain Inhibitor

et al. 2018

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We report the structure-based discovery of CF53 (28) as a highly potent and orally active inhibitor of bromodomain and extra-terminal (BET) proteins. By the incorporation of a NH-pyrazole group into the 9H-pyrimido[4,5- b]indole core, we identified a series of compounds that bind to BRD4 BD1 protein with K values of <1 nM and achieve low nanomolar potencies in the cell growth inhibition of leukemia and breast cancer cells. The most-promising compound, CF53, possesses excellent oral pharmacokinetic properties and achieves significant antitumor activity in both triple-negative breast cancer and acute leukemia xenograft models in mice. Determination of the co-crystal structure of CF53 with the BRD4 BD1 protein provides a structural basis for its high binding affinity to BET proteins. CF53 is very selective over non-BET bromodomain-containing proteins. These data establish CF53 as a potent, selective, and orally active BET inhibitor, which warrants further evaluation for advanced preclinical development.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Structure-Based Discovery of CF53 as a Potent and Orally Bioavailable Bromodomain and Extra-Terminal (BET) Bromodomain Inhibitor

et al. 2018

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“…Most boronic acids or pinacolboronic esters are commercially available. Others were synthesized according to known methods reported previously. − Suzuki coupling ,, of the corresponding boronic acids or pinacolboronic esters and 7 or S10 followed by reverse phase HPLC purification furnished pure final products as salts of trifluoroacetic acid.…”

Section: Chemistrymentioning

confidence: 99%

“…Others were synthesized according to known methods reported previously. 37−39 Suzuki coupling 37,40,41 of the corresponding boronic acids or pinacolboronic esters and 7 or S10…”

Section: ■ Chemistrymentioning

confidence: 99%

Structure-Based Discovery of 4-(6-Methoxy-2-methyl-4-(quinolin-4-yl)-9H-pyrimido[4,5-b]indol-7-yl)-3,5-dimethylisoxazole (CD161) as a Potent and Orally Bioavailable BET Bromodomain Inhibitor

et al. 2017

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We have designed and synthesized 9H-pyrimido[4,5-b]indole-containing compounds to obtain potent and orally bioavailable BET inhibitors. By incorporation of an indole or a quinoline moiety to the 9H-pyrimido[4,5-b]indole core, we identified a series of small molecules showing high binding affinities to BET proteins and low nanomolar potencies in inhibition of cell growth in acute leukemia cell lines. One such compound, 4-(6-methoxy-2-methyl-4-(quinolin-4-yl)-9H-pyrimido[4,5-b]indol-7-yl)-3,5-dimethylisoxazole (31) has excellent microsomal stability and good oral pharmacokinetics in rats and mice. Orally administered, 31 achieves significant antitumor activity in the MV4;11 leukemia and MDA-MB-231 triple-negative breast cancer xenograft models in mice. Determination of the cocrystal structure of 31 with BRD4 BD2 provides a structural basis for its high binding affinity to BET proteins. Testing its binding affinities against other bromodomain-containing proteins shows that 31 is a highly selective inhibitor of BET proteins. Our data show that 31 is a potent, selective, and orally active BET inhibitor.

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“…Recently, many pharmacologically important compounds with substituents at the 4-position of indazole have been developed for pre-clinical testing, such as ABT-869 17 and ABT-102. 18,19 Reliable and efficient syntheses of these indazoles were required to provide access to large quantities of bulk drug for further studies.…”

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confidence: 99%