Wednesday, February 5, 2025
2/5/2025
PROJECT SUMMARY Although dysregulated gene transcription is a major contributing factor in cancer, the development of drugs interfering with general transcription remains a challenging task. The bromodomain-containing protein TAF1 is the largest component of the multiprotein assembly TFIID, a highly dynamic complex that serves as a general transcription factor for transcription initiation in eukaryotes. Recently it was reported that TAF1 has a critical role in AML1-ETO driven acute myeloid leukemia (AML), whereas TAF1 perturbation had little effect on normal hematopoietic stem cells, implying that TAF1 has the potential to serve as a therapeutic target for AML. Current approaches to target TAF1 are limited to monovalent small molecule inhibitors of the bromodomain, including the highly selective and potent Genentech inhibitor GNE-371 and the Astra Zeneca ATR inhibitor AZD6738 (ceralasertib), which we recently reported as a dual TAF1-ATR inhibitor. However, our own data along with previously reported observations support the notion that such bromodomain inhibitors lack cancer cell kill potential as judged by cell proliferation, induction of apoptosis, p53 and DNA damage signaling studies. As such, TAF1 is an underexplored potential drug target and no TAF1 inhibitor has reached the clinic. To target TAF1 more efficiently, we applied a structure-guided approach and generated different series of cereblon (CRBN) directed PROTAC (proteolysis targeting chimera) degraders of TAF1. Early lead PROTACs are highly effective against AML and other blood cancer cell lines with complete degradation of TAF1 at concentrations as low as 1 nM, and induction of apoptosis. TAF1 depletion and cell survival can be rescued by monovalent inhibitors or non-degradable TAF1 mutant expression, indicating on-target activity. Low doses of an in vivo active PROTAC demonstrated significant inhibition of AML tumor xenograft growth and compatibility with long-term survival. Supported by preliminary data, the central hypothesis of this proposal is that targeted degradation of TAF1 is a viable strategy to combat AML and other cancers vulnerable to TAF1 depletion. Our objective is to develop first- in-class TAF1-selective PROTACs and to explore their therapeutic potential. The rationale underlying this research is that it will provide general insights into the feasibility of TAF1 as a cancer target and build a new scientific framework whereby new strategies to cancer therapies can be developed. Our approach utilizes methods in structural biology, medicinal chemistry, and cancer biology, performed by an interdisciplinary team of researchers and clinician scientists.
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