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

• Published in: European journal of medicinal chemistry Vol. 251; no. C; p. 115246
• Main Authors: Koravovic, Mladen, Mayasundari, Anand, Tasic, Gordana, Keramatnia, Fatemeh, Stachowski, Timothy R., Cui, Huarui, Chai, Sergio C., Jonchere, Barbara, Yang, Lei, Li, Yong, Fu, Xiang, Hiltenbrand, Ryan, Paul, Leena, Mishra, Vibhor, Klco, Jeffery M., Roussel, Martine F., Pomerantz, William CK, Fischer, Marcus, Rankovic, Zoran, Savic, Vladimir
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 05.05.2023; Elsevier
• Subjects: Amides; BET inhibitors; Cell Cycle Proteins - metabolism; Cell Line; Chemistry, Medicinal; JQ1; Life Sciences & Biomedicine; Nuclear Proteins - metabolism; Pharmacology & Pharmacy; Science & Technology; Transcription Factors - metabolism; Amides; JQ1; BET inhibitors; PERMEABILITY; MECHANISM; ACETYL-LYSINE RECOGNITION; DRUG DISCOVERY; HISTONE ACETYLATION; MOTIF; SOLUBILITY; BROMODOMAIN PROTEINS; BIOISOSTERES; TARGETS
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2023.115246

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. [Display omitted] •A PROTAC X-ray structure inspired synthesis of JQ1-based heteroaromatic amides.•Best derivatives showed improved overall profile compared to JQ1 and birabresib.•X-ray structure of SJ1461-BRD4 complex provided a rationale for improved affinity.•SJ1461 is being evaluated as a potential clinical candidate.