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Chemical Structure| 1793016-39-3 Chemical Structure| 1793016-39-3

Structure of 1793016-39-3

Chemical Structure| 1793016-39-3

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Yangfeng Li ; Zhengnan Shen ; Kiira Ratia ; Jiong Zhao ; Fei Huang ; Oleksii Dubrovyskyii , et al.

Abstract: The bromodomain and extra-terminal domain (BET) proteins are epigenetic readers, regulating transcription via two highly homologous tandem bromodomains, BD1 and BD2. Clinical development of nonselective pan-BD BET inhibitors has been challenging, partly due to dose-limiting side effects such as thrombocytopenia. This has prompted the push for domain-selective BET inhibitors to achieve a more favorable therapeutic window. We report a structure-guided drug design campaign that led to the development of a potent BD1-selective BET inhibitor, 33 (XL-126), with a Kd of 8.9 nM and 185-fold BD1/BD2 selectivity. The high selectivity was first assayed by SPR, validated by a secondary time-resolved fluorescence energy transfer assay, and further corroborated by BROMOscan (∼57–373 fold selectivity). The cocrystal of 33 with BRD4 BD1 and BD2 demonstrates the source of selectivity: repulsion with His437 and lost binding with the clamp. Notably, the BD1 selectivity of BET inhibitor 33 leads to both the preservation of platelets and potent anti-inflammatory efficacy.

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Product Details of [ 1793016-39-3 ]

CAS No. :1793016-39-3
Formula : C12H19BN2O3
M.W : 250.10
SMILES Code : CN1C(C(N)=CC(B2OC(C)(C(C)(O2)C)C)=C1)=O

Safety of [ 1793016-39-3 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319
Precautionary Statements:P501-P270-P264-P280-P302+P352-P337+P313-P305+P351+P338-P362+P364-P332+P313-P301+P312+P330
 

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