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From PROTAC to inhibitor: Structure-guided discovery of potent and orally bioavailable BET inhibitors

An X-ray structure of a CLICK chemistry-based BET PROTAC bound to BRD2(BD2) inspired synthesis of JQ1 derived heterocyclic amides. This effort led to the discovery of potent BET inhibitors displaying overall improved profiles when compared to JQ1 and birabresib. A thiadiazole derived 1q (SJ1461) displayed excellent BRD4 and BRD2 affinity and high potency in the panel of acute leukaemia and medulloblastoma cell lines. A structure of 1q co-crystalised with BRD4-BD1 revealed polar interactions with the AZ/BC loops, in particular with Asn140 and Tyr139, rationalising the observed affinity improvements. In addition, exploration of pharmacokinetic properties of this class of compounds suggest that the heterocyclic amide moiety improves drug-like features. Our study led to the discovery of potent and orally bioavailable BET inhibitor 1q (SJ1461) as a promising candidate for further development.

 

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The passage describes a research effort that resulted in the discovery of a new, potent BET inhibitor called 1q (SJ1461) that shows improved profiles compared to existing BET inhibitors such as JQ1 and birabresib. The researchers used a CLICK chemistry-based approach to synthesize JQ1-derived heterocyclic amides and discovered that a thiadiazole derived compound, 1q, displayed excellent affinity for both BRD4 and BRD2, as well as high potency in a panel of acute leukemia and medulloblastoma cell lines.

The researchers also conducted a co-crystallization study of 1q with BRD4-BD1 and found that the compound interacted with the AZ/BC loops, particularly with Asn140 and Tyr139, which helps to explain its affinity improvements. Additionally, the researchers explored the pharmacokinetic properties of this class of compounds and found that the heterocyclic amide moiety improves drug-like features.

Overall, this study highlights the potential of using CLICK chemistry-based approaches to discover new, potent BET inhibitors with improved profiles compared to existing inhibitors. The discovery of 1q as a promising candidate for further development underscores the importance of continued research in this area for the development of new cancer therapies.

Related Products

Cat.No. Product Name Information
S7360 Birabresib (OTX015) Birabresib (OTX015, MK 8628) is a potent BET bromodomain inhibitor with EC50 ranging from 10 to 19 nM for BRD2, BRD3, and BRD4 in cell-free assays. Birabresib inhibits the expression of Nuclear receptor binding SET domain protein 3 (NSD3) target genes.

Related Targets

Epigenetic Reader Domain NSD