PROTAC-mediated degradation of TAF1 induces apoptosis in AML cells and inhibits tumor growth in vivo

ABSTRACT: The bromodomain-containing protein, TAF1 (TFII-250), is the largest component of the multiprotein assembly TFIID, a dynamic complex that serves as a general factor for transcription initiation. CRISPR and RNAi screens of pan cancer cell lines revealed TAF1 is broadly required for optimal cell growth and survival, but a subset of cell lines showed enhanced TAF1 dependence. These observations suggest that TAF1 has the potential to serve as a therapeutic target in sensitive tumors. Current approaches employed to target TAF1 are limited to monovalent small molecule inhibitors of the bromodomain. However, recent studies showed that such inhibitors lack cancer cell kill potential. We applied a structure-guided approach to generate cereblon (CRBN) recruiting PROTAC degraders of TAF1 using the chemical scaffolds of ceralasertib and GNE371. We present evidence that GNE371-based PROTACs are effective in degradation of TAF1 at concentrations as low as 1 nM. TAF1 depletion activated p53 and induced apoptosis in AML cell lines and certain solid tumor cells. An in vivo active TAF1 PROTAC inhibited the growth of AML tumor xenograft. The results showed that inhibition of bromodomain is not sufficient to inactivate TAF1 functions, while a PROTAC approach induces strong biological effects. Furthermore, TAF1 PROTACs have therapeutic potential against AML and other sensitive tumors.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Myeloid Cell

DISEASE(S): Acute Leukemia

SUBMITTER: John Koomen  

LAB HEAD: Jiandong Chen

PROVIDER: PXD061282 | Pride | 2025-02-28

REPOSITORIES: pride