ABSTRACT
The transcriptional coactivator cAMP response element binding protein (CREB)-binding protein (CBP) and its homologue p300 have emerged as attractive therapeutic targets for human cancers such as acute myeloid leukemia (AML). Herein, we report the design, synthesis, and biological evaluation of a series of cereblon (CRBN)-recruiting CBP/p300 proteolysis targeting chimeras (PROTACs) based on the inhibitor CCS1477. The representative compounds 14g (XYD190) and 14h (XYD198) potently inhibited the growth of AML cells with low nanomolar IC50 values and effectively degraded CBP and p300 proteins in a concentration- and time-dependent manner. Mechanistic studies confirmed that 14g and 14h can selectively bind to CBP/p300 bromodomains and induce CBP and p300 degradation in bromodomain family proteins in a CRBN- and proteasome-dependent manner. 14g and 14h displayed remarkable antitumor efficacy in the MV4;11 xenograft model (TGI = 88% and 93%, respectively). Our findings demonstrated that 14g and 14h are useful lead compounds and deserve further optimization and activity evaluation for the treatment of human cancers.
Subject(s)
Antineoplastic Agents , Proteolysis , Humans , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Animals , Mice , Proteolysis/drug effects , Cell Line, Tumor , E1A-Associated p300 Protein/metabolism , E1A-Associated p300 Protein/antagonists & inhibitors , CREB-Binding Protein/metabolism , CREB-Binding Protein/antagonists & inhibitors , Drug Discovery , Xenograft Model Antitumor Assays , Structure-Activity Relationship , p300-CBP Transcription Factors/metabolism , p300-CBP Transcription Factors/antagonists & inhibitors , Cell Proliferation/drug effects , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/metabolism , Leukemia, Myeloid, Acute/pathology , Mice, NudeABSTRACT
The bromodomain of CREB (cyclic-AMP response element binding protein) binding protein (CBP) is an epigenetic "reader" and plays a key role in transcriptional regulation. CBP bromodomain is considered to be a promising therapeutic target for acute myeloid leukemia (AML). Herein, we report the discovery of a series of 1-(indolizin-3-yl)ethan-1-one derivatives as potent, and selective CBP bromodomain inhibitors focused on improving cellular potency. One of the most promising compounds, 7e (Y08262), inhibits the CBP bromodomain at the nanomolar level (IC50 = 73.1 nM) with remarkable selectivity. In addition, the new inhibitor also displays potent inhibitory activities in AML cell lines. Collectively, this study provides a new lead compound for further validation of CBP bromodomain as a molecular target for AML drug development.
Subject(s)
Leukemia, Myeloid, Acute , Humans , Protein Domains , Leukemia, Myeloid, Acute/drug therapy , Cell Line, TumorABSTRACT
Inhibition of the bromodomain of the CREB (cyclic-AMP response element-binding protein) binding protein (CBP) is a particularly promising new therapeutic approach for cancer. Benzimidazole derivatives CCS1477 and its analogues (8 and 9) are highly potent and selective CBP bromodomain inhibitors, with Kd values of 26.4, 37.0, and 34.3 nM in ITC assay, respectively. Among these compounds, CCS1477 is undergoing phase Ib/IIa clinical trials for the treatment of various cancers. Thus, we determined the co-crystal structures of CCS1477 and its analogues in complex with CBP bromodomain and revealed the detailed binding modes. Furthermore, overlapping with other reported co-crystal structures allowed us to identify that interaction with Arg1173, LPF shelf, and ZA channel was critical for keeping strong biological activity and selectivity. Collectively, this study provided a structural basis for CBP bromodomain inhibitors design.
Subject(s)
CREB-Binding Protein , Enzyme Inhibitors , CREB-Binding Protein/metabolism , Protein Binding , Protein DomainsABSTRACT
TRIM24 (tripartite motif-containing protein 24) and BRPF1 (bromodomain and PHD finger containing protein 1) are epigenetics "readers" and potential therapeutic targets for cancer and other diseases. Here we describe the structure-guided design of 1-(indolin-1-yl)ethan-1-ones as novel TRIM24/BRPF1 bromodomain inhibitors. The representative compound 20l (Y08624) is a new TRIM24/BRPF1 dual inhibitor, with IC50 values of 0.98 and 1.16 µM, respectively. Cellular activity of 20l was validated by viability assay in prostate cancer (PC) cell lines. In PC xenograft models, 20l suppressed tumor growth (50 mg/kg/day, TGI = 53%) without exhibiting noticeable toxicity. Compound 20l represents a versatile starting point for the development of more potent TRIM24/BRPF1 inhibitors.
Subject(s)
Adaptor Proteins, Signal Transducing , Carrier Proteins , DNA-Binding Proteins , Adaptor Proteins, Signal Transducing/antagonists & inhibitors , Animals , Carrier Proteins/antagonists & inhibitors , Cell Line, Tumor , DNA-Binding Proteins/antagonists & inhibitors , Humans , Male , Prostatic Neoplasms/drug therapy , Protein DomainsABSTRACT
CREB (cyclic-AMP responsive element binding protein) binding protein (CBP) is a potential target for prostate cancer treatment. Herein, we report the structural optimization of a series of 1-(indolizin-3-yl)ethan-1-one compounds as new selective CBP bromodomain inhibitors, aiming to improve cellular potency and metabolic stability. This process led to compound 9g (Y08284), which possesses good liver microsomal stability and pharmacokinetic properties (F = 25.9%). Furthermore, the compound is able to inhibit CBP bromodomain as well as the proliferation, colony formation, and migration of prostate cancer cells. Additionally, the new inhibitor shows promising antitumor efficacy in a 22Rv1 xenograft model (TGI = 88%). This study provides new lead compounds for further development of drugs for the treatment of prostate cancer.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , CREB-Binding Protein/antagonists & inhibitors , Indolizidines/chemical synthesis , Prostatic Neoplasms/drug therapy , Animals , Antineoplastic Agents/pharmacokinetics , Caco-2 Cells , Cell Line, Tumor , Drug Design , Humans , Indolizidines/pharmacokinetics , Indolizidines/pharmacology , Male , Mice , Mice, SCID , Microsomes, Liver , Models, Molecular , Molecular Docking Simulation , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Tumor Stem Cell Assay , Xenograft Model Antitumor AssaysABSTRACT
Tripartite motif-containing protein 24 (TRIM24), recognized as an epigenetic reader for acetylated H3K23 (H3K23ac) via its bromodomain, has been closely involved in tumorigenesis or tumor progression of several cancers. Developing inhibitors of TRIM24 is significant for functional studies and drug discovery. Herein, we report the identification, optimization and evaluation of N-benzyl-3,6-dimethylbenzo[d]isoxazol-5-amines as TRIM24 bromodomain inhibitors starting from an in house library screening. Structure-based optimization leads to two potent and selective compounds 11d and 11h in an Alphascreen assay with IC50 values of 1.88⯵M and 2.53⯵M, respectively. The viability assay demonstrates the great potential of this series of compounds as inhibitors of proliferation of prostate cancer (PC) cells LNCaP, C4-2B. A colony formation assay further supports this inhibitory activity. Compounds 11d and 11h inhibit cell proliferation of other cancer types such as non-small cell lung cancer (NSCLC) cells A549 with IC50 values of 1.08⯵M and 0.75⯵M, respectively. These data suggests that compounds 11d and 11h are promising lead compounds for further research.
