Discovery of a Novel Bromodomain and Extra Terminal Domain (BET) Protein Inhibitor, I-BET282E, Suitable for Clinical Progression

The functions of the bromodomain and extra terminal (BET) family of proteins have been implicated in a wide range of diseases, particularly in the oncology and immuno-inflammatory areas, and several inhibitors are under investigation in the clinic. To mitigate the risk of attrition of these compound...

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Veröffentlicht in:	Journal of medicinal chemistry 2021-08, Vol.64 (16), p.12200-12227
Hauptverfasser:	Jones, Katherine L, Beaumont, Dominic M, Bernard, Sharon G, Bit, Rino A, Campbell, Simon P, Chung, Chun-Wa, Cutler, Leanne, Demont, Emmanuel H, Dennis, Kate, Gordon, Laurie, Gray, James R, Haase, Michael V, Lewis, Antonia J, McCleary, Scott, Mitchell, Darren J, Moore, Susanne M, Parr, Nigel, Robb, Olivia J, Smithers, Nicholas, Soden, Peter E, Suckling, Colin J, Taylor, Simon, Walker, Ann L, Watson, Robert J, Prinjha, Rab K
Format:	Artikel
Sprache:	eng
Schlagworte:	Animals Anti-Inflammatory Agents - chemical synthesis Anti-Inflammatory Agents - metabolism Anti-Inflammatory Agents - therapeutic use Arthritis - chemically induced Arthritis - drug therapy Collagen Crystallography, X-Ray Dogs Female Imidazoles - chemical synthesis Imidazoles - metabolism Imidazoles - therapeutic use Male Mice Molecular Structure Nuclear Proteins - antagonists & inhibitors Nuclear Proteins - chemistry Nuclear Proteins - metabolism Protein Binding Protein Domains Quinolines - chemical synthesis Quinolines - metabolism Quinolines - therapeutic use Rats Rats, Inbred Lew Rats, Wistar Structure-Activity Relationship Transcription Factors - antagonists & inhibitors Transcription Factors - chemistry Transcription Factors - metabolism
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Zusammenfassung:	The functions of the bromodomain and extra terminal (BET) family of proteins have been implicated in a wide range of diseases, particularly in the oncology and immuno-inflammatory areas, and several inhibitors are under investigation in the clinic. To mitigate the risk of attrition of these compounds due to structurally related toxicity findings, additional molecules from distinct chemical series were required. Here we describe the structure- and property-based optimization of the tool molecule I-BET151 toward I-BET282E, a molecule with properties suitable for progression into clinical studies.
ISSN:	0022-2623 1520-4804
DOI:	10.1021/acs.jmedchem.1c00855