The
bromodomain and extra-terminal (BET) family proteins, consisting
of BRD2, BRD3, BRD4, and testis-specific BRDT members, are epigenetic
“readers” and play a key role in the regulation of gene
transcription. BET proteins are considered to be attractive therapeutic
targets for cancer and other human diseases. Recently, heterobifunctional
small-molecule BET degraders have been designed based upon the proteolysis
targeting chimera (PROTAC) concept to induce BET protein degradation.
Herein, we present our design, synthesis, and evaluation of a new
class of PROTAC BET degraders. One of the most promising compounds, 23, effectively degrades BRD4 protein at concentrations as
low as 30 pM in the RS4;11 leukemia cell line, achieves an IC50 value of 51 pM in inhibition of RS4;11 cell growth and induces
rapid tumor regression in vivo against RS4;11 xenograft tumors. These
data establish that compound 23 (BETd-260/ZBC260) is
a highly potent and efficacious BET
degrader.
Proteins of the bromodomain and extra-terminal (BET) family are epigenetics "readers" and promising therapeutic targets for cancer and other human diseases. We describe herein a structure-guided design of [1,4]oxazepines as a new class of BET inhibitors and our subsequent design, synthesis, and evaluation of proteolysis-targeting chimeric (PROTAC) small-molecule BET degraders. Our efforts have led to the discovery of extremely potent BET degraders, exemplified by QCA570, which effectively induces degradation of BET proteins and inhibits cell growth in human acute leukemia cell lines even at low picomolar concentrations. QCA570 achieves complete and durable tumor regression in leukemia xenograft models in mice at well-tolerated dose-schedules. QCA570 is the most potent and efficacious BET degrader reported to date.
The
estrogen receptor (ER) is a validated target for the treatment
of estrogen receptor-positive (ER+) breast cancer. Here, we describe
the design, synthesis, and extensive structure–activity relationship
(SAR) studies of small-molecule ERα degraders based on the proteolysis
targeting chimeras (PROTAC) concept. Our efforts have resulted in
the discovery of highly potent and effective PROTAC ER degraders,
as exemplified by ERD-308 (32). ERD-308 achieves DC50 (concentration causing 50% of protein degradation) values
of 0.17 and 0.43 nM in MCF-7 and T47D ER+ breast cancer cell lines,
respectively, and induces >95% of ER degradation at concentrations
as low as 5 nM in both cell lines. Significantly, ERD-308 induces
more complete ER degradation than fulvestrant, the only approved selective
ER degrader (SERD), and is more effective in inhibition of cell proliferation
than fulvestrant in MCF-7 cells. Further optimization of ERD-308 may
lead to a new therapy for advanced ER+ breast cancer.
Triple-negative breast cancers (TNBC) remain clinically challenging with a lack of options for targeted therapy. In this study, we report the development of a second-generation BET bromodomain (BRD) inhibitor, BETd-246, which exhibits superior selectivity, potency and antitumor activity. In human TNBC cells, BETd-246 induced degradation of BET transcription factors at low nanomolar concentrations within 1 hr of exposure, resulting in robust growth inhibition and apoptosis. BETd-246 was more potent and effective in TNBC cells than its parental BET inhibitor compound BETi-211. RNA-seq analysis revealed predominant downregulation of a large number of genes involved in proliferation and apoptosis in cells treated with BETd-246, as compared to BETi-211 treatment which upregulated and downregulated a similar number of genes. Functional investigations identified the MCL1 gene as a critical downstream effector of these BET degraders, which synergized with small molecule inhibitors of BCL-xL in triggering apoptosis. In multiple murine xenograft models of human breast cancer, BETd-246 and a further optimized analogue BETd-260 effectively depleted BET proteins in tumors and exhibited strong antitumor activities at well-tolerated dosing schedules. Overall, our findings show how specific targeting of BET proteins for degradation yields an effective therapeutic strategy for TNBC treatment.
Pharmacological inhibition of histone deacetylases (HDACs) has been successfully applied in the treatment of a wide range of disorders, including Parkinson's disease, infection, cardiac diseases, inflammation, and especially cancer. HDAC inhibitors (HDACIs) have been proved to be effective antitumor agents by various stages of investigation. At present, there are two opposite focuses of HDACI design in the cancer therapy, highly selective inhibitor strategy and dual- or multitargeted inhibitors. The former method, which is supposed to elucidate the function of individual HDAC and provide candidate inhibitors with fewer side effects, has been widely accepted by the inhibitor developer. The latter approach, though less practiced, has promising potential for the antitumor therapy based on HDACIs. Effective HDACIs, some of which are in clinic anticancer research, have been developed by both methods. In order to gain insight into HDACI design, the strategies and achievements of the two diverse methods are reviewed.
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