Discovery of Dual TAF1-ATR Inhibitors and Ligand-Induced Structural Changes of the TAF1 Tandem Bromodomain

Bromodomains regulate chromatin remodeling and gene transcription through recognition of acetylated lysines on histones and other proteins. Bromodomain-containing protein TAF1, a subunit of general transcription factor TFIID, initiates preinitiation complex formation and cellular transcription. TAF1 serves as a cofactor for certain oncogenic transcription factors and is implicated in regulating the p53 tumor suppressor. Therefore, TAF1 is a potential target to develop small molecule therapeutics for diseases arising from dysregulated transcription, such as cancer. Here, we report the ATR kinase inhibitor AZD6738 (Ceralasertib) and analogues thereof as bona fide inhibitors of TAF1. Crystallo-graphic and small-angle X-ray scattering studies established that newly identified and previously reported inhibitors stabilize distinct structural states of the TAF1 tandem bromodomain through open-closed transitions and dimerization. Combined with functional studies on p53 signaling in cancer cell lines, the data provide new insights into the feasibility and challenges of TAF1 inhibitors as chemical probes and therapeutics.

Automated summary

Bromodomains play a regulatory role in chromatin remodeling and gene transcription by recognizing acetylated lysines. TAF1, a protein containing Bromodomain, is a crucial component in the formation of preinitiation complex and cellular transcription. It also acts as a cofactor for oncogenic transcription factors and is involved in regulating the p53 tumor suppressor. Therefore, TAF1 could be a potential target for developing small molecule therapeutics for diseases associated with dysregulated transcription, such as cancer. The ATR kinase inhibitor AZD6738 and its analogues have been identified as effective inhibitors of TAF1, and their mechanism of action has been elucidated through crystallographic and small-angle X-ray scattering studies.