Triple-negative breast cancer (TNBC) is a heterogeneous breast cancer subtype with poor prognoses and limited therapeutic options. The TATA-box binding protein associated factor 1 (TAF1) is an essential protein involved in the transcriptional regulation of cancer development and progress. However, the therapeutic potential and underlying mechanism of targeting TAF1 in TNBC remain unknown. Here, using chemical probe BAY-299, we identify that TAF1 inhibition leads to the induction of endogenous retrovirus (ERVs) expression and double-stranded RNA (dsRNA) formation, resulting in the activation of interferon responses and cell growth suppression in a subset of TNBC, resembling anti-viral mimicry effect. This correlation between TAF1 and interferon signature was validated in three independent breast cancer patient datasets. Furthermore, we observe heterogeneous responses to TAF1 inhibition across a set of TNBC cell lines. By integrating transcriptome and proteome data, we demonstrate that high levels of proliferating cell nuclear antigen (PCNA) protein serve as a predictive biomarker associated with suppressive tumor immune responses in various cancers, which may limit the efficiency of TAF1 inhibition.

01 Dec 2021·Translational Cancer ResearchQ4 · MEDICINE

TAF1 inhibitor Bay-299 induces cell death in acute myeloid leukemia

Q4 · MEDICINE

Article

Author: Yao, Qi ; Zhou, Lixin ; Chen, Jieping ; Li, Hui ; Ma, Le

BACKGROUNDAcute myeloid leukemia (AML) is one of the most common hematopoietic malignancies. The cure rate of currently intensive chemotherapy in AML was only 40% or less, and there is an urgent need to develop novel effective therapeutic targets or drugs. The TATA-box binding protein associated factor 1 (TAF1) plays important roles in transcriptional regulation and leukemogenesis. However, the potential of TAF1 as a therapeutic target for AML remains unclear. The present study examined the effects of the TAF1 inhibitor Bay-299 on AML cells and the underlying molecular mechanisms.METHODSThe expression of TAF1 in various types of tumors was analyzed using The Cancer Genome Atlas (TCGA) and the UALCAN database. The effects of Bay-299 on cell proliferation were evaluated using the Cell Counting Kit-8 (CCK-8) assay. Cell death, EdU incorporation, and cell differentiation were detected using flow cytometry. Western blot analysis was utilized to confirm the activation of the apoptotic pathway. Expression of cell cycle and cell death-related genes was analyzed by quantitative real-time polymerase chain reaction (qRT-PCR).RESULTSAnalysis of the public databases showed that TAF1 expression was elevated in multiple types of tumors. Treatment of AML cells with the TAF1 inhibitor Bay-299 resulted in a remarkable inhibition of cell growth, increased cell death, reduced Edu incorporation, and increased cell differentiation. The apoptosis inhibitor Z-VAD and the receptor-interacting protein kinase 1 (RIPK1) inhibitor Nec-2 could rescue cell death induced by Bay-299. Bay-299 treatment increased the cleavage of key pro-apoptotic proteins, and this effect was ameliorated by administration of Z-VAD and Nec-2. Moreover, Bay-299 treatment was associated with increased expression of cell cycle inhibitor genes and multiple pyroptosis-promoting genes, contributing to the phenotypes observed in AML cell lines.CONCLUSIONSThe TAF1 inhibitor Bay-299 induced AML cell death through multiple mechanisms and may be a promising candidate for the treatment of patients with AML.

11 May 2017·Journal of Medicinal ChemistryQ1 · MEDICINE

Benzoisoquinolinediones as Potent and Selective Inhibitors of BRPF2 and TAF1/TAF1L Bromodomains

Q1 · MEDICINE

Article

Author: Meier, Julia ; Bennett, James ; Müller, Susanne ; ter Laak, Antonius ; Monteiro, Octovia ; Huber, Kilian V. M. ; Díaz-Sáez, Laura ; Siegel, Stephan ; Pütter, Vera ; Haendler, Bernard ; Hartung, Ingo V. ; Sugawara, Tatsuo ; Bouché, Léa ; Tallant, Cynthia ; Fedorov, Oleg ; Stöckigt, Detlef ; Siejka, Paulina ; Christ, Clara D. ; Holton, Simon J. ; Weiske, Jörg ; Fernández-Montalván, Amaury E.

Bromodomains (BD) are readers of lysine acetylation marks present in numerous proteins associated with chromatin. Here we describe a dual inhibitor of the bromodomain and PHD finger (BRPF) family member BRPF2 and the TATA box binding protein-associated factors TAF1 and TAF1L. These proteins are found in large chromatin complexes and play important roles in transcription regulation. The substituted benzoisoquinolinedione series was identified by high-throughput screening, and subsequent structure-activity relationship optimization allowed generation of low nanomolar BRPF2 BD inhibitors with strong selectivity against BRPF1 and BRPF3 BDs. In addition, a strong inhibition of TAF1/TAF1L BD2 was measured for most derivatives. The best compound of the series was BAY-299, which is a very potent, dual inhibitor with an IC₅₀ of 67 nM for BRPF2 BD, 8 nM for TAF1 BD2, and 106 nM for TAF1L BD2. Importantly, no activity was measured for BRD4 BDs. Furthermore, cellular activity was evidenced using a BRPF2- or TAF1-histone H3.3 or H4 interaction assay.

100 Deals associated with BAY-299

R&D Status

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Acute Myeloid Leukemia	Discovery	DE	Third Military Medical University	-
Neoplasms	Discovery	DE	Bayer AG	-

Clinical Result

Indication

Phase

Evaluation

View All Results

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Deal

Boost your decision using our deal data.

view full example data

Core Patent

Boost your research with our Core Patent data.

view full example data

Clinical Trial

Identify the latest clinical trials across global registries.

view full example data

Approval

Accelerate your research with the latest regulatory approval information.

view full example data

Regulation

Understand key drug designations in just a few clicks with Synapse.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis


No Data

BAY-299

Overview

Basic Info

Structure

Related

R&D Status

Clinical Result

Translational Medicine

Deal

Core Patent

Clinical Trial

Approval

Regulation