RARE DISEASE
Cat-eye syndrome
Cat-eye syndrome
Cat-eye syndrome
Synonyms: CES
Synonyms: CES
Synonyms: CES
Drug discovery
16
papers
On emerging therapies
Overview
Cat-eye syndrome (CES) is a rare chromosomal disorder caused by partial tetrasomy or trisomy of chromosome 22q11.1-q11.21, leading to variable clinical features such as iris coloboma (absent in ~50%), preauricular skin tags/pits, anal atresia, cardiac/renal anomalies, and mild developmental delays [1][2][4][11]. Diagnosis relies on cytogenetic analysis (karyotyping/FISH) and clinical evaluation [1][4][6]. Management is symptom-focused, requiring multispecialty collaboration [3][8][15].
Therapies
Surgical interventions: Correct anal/intestinal atresia, cardiac defects, cleft palate, or skeletal abnormalities [1][6][8]
Rehabilitative support: Physical, occupational, and speech therapy for developmental delays [1][3][6]
Organ-specific management: Cardiac monitoring, nephrological care, and ophthalmologic interventions (e.g., coloboma repair) [3][8][13]
Categories: rare abdominal surgical diseases, rare developmental anomalies during embryogenesis, rare genetic diseases, rare ophthalmic disorders, rare renal diseases, rare transplant-related disorders
Research Papers
16 drug discovery papers about Cat-eye syndrome. Recent publications:
16 drug discovery papers about Cat-eye syndrome. Recent publications:
categories:
Small molecules
small molecules
2024-12-23 | The CECR2 bromodomain displays distinct binding modes to select for acetylated histone proteins versus non-histone ligands.
The cat eye syndrome chromosome region candidate 2 (CECR2) protein is an epigenetic regulator involved in chromatin remodeling and transcriptional control. The CECR2 bromodomain (CECR2-BRD) plays a pivotal role in directing the activity of CECR2 through its capacity to recognize and bind acetylated lysine residues on histone proteins. This study elucidates the binding specificity and structural mechanisms of CECR2-BRD interactions with both histone and non-histone ligands, employing techniques such as isothermal titration calorimetry (ITC), nuclear magnetic resonance (NMR) spectroscopy, and a high-throughput peptide assay. The CECR2-BRD selectively binds acetylated histone H3 and H4 ligands, exhibiting a preference for multi-acetylated over mono-acetylated targets. The highest affinity was observed for tetra-acetylated histone H4. Neighboring post-translational modifications, including methylation and phosphorylation, modulate acetyllysine recognition, with significant effects observed for histone H3 ligands. Additionally, this study explored the interaction of the CECR2-BRD with the acetylated RelA subunit of NF-κB, a pivotal transcription factor in inflammatory signaling. Dysregulated NF-κB signaling is implicated in numerous pathologies, including cancer progression, with acetylation of RelA at lysine 310 (K310ac) being critical for its transcriptional activity. Recent evidence linking the CECR2-BRD to RelA suggests it plays a role in inflammatory and metastatic pathways, underscoring the need to understand the molecular basis of this interaction. We found the CECR2-BRD binds to acetylated RelA with micromolar affinity, and uses a distinctive binding mode to recognize this non-histone ligand. These results provide new insight on the role of CECR2 in regulating NF-κB-mediated inflammatory pathways. Functional mutagenesis of critical residues, such as Asn514 and Asp464, highlight their roles in ligand specificity and binding dynamics. Notably, the CECR2-BRD remained monomeric in solution and exhibited differential conformational responses upon ligand binding, suggesting adaptive recognition mechanisms. Furthermore, the CECR2-BRD exclusively interacts with nucleosome substrates containing multi-acetylated histones, emphasizing its role in transcriptional activation within euchromatic regions. These findings position the CECR2-BRD as a key chromatin reader and a promising therapeutic target for modulating transcriptional and inflammatory processes, particularly through the development of selective bromodomain inhibitors.
2022-05-02 | Discovery of a highly potent CECR2 bromodomain inhibitor with 7H-pyrrolo[2,3-d] pyrimidine scaffold.
Cat eye syndrome chromosome region candidate 2 (CECR2) bromodomain is a module of CECR2-containing remodeling factor (CERF), which is a chromatin remodeling complex correlating with transcriptional control and adjustment of chromatin architecture. Potent chemical probes would be beneficial to gain insights into the biochemical and pharmacological functions of CECR2 BRD. Herein, we report the discovery of a series of CECR2 BRD inhibitors with 7H-pyrrolo[2,3-d] pyrimidine scaffold based on molecular docking model of TP-248 and CECR2 BRD. The most potent inhibitor of this series, DC-CBi-22 with IC50 of 8.0 ± 1.4 nM against CECR2 BRD and selectivity over BPTF BRD up to 24.9-fold. The SARs were detailed according to molecular docking. DC-CBi-22 would serve as a useful chemical probe for the study of CECR2.
2021-01-07 | Cytotoxic activity of bromodomain inhibitor NVS-CECR2-1 on human cancer cells.
Bromodomain (BRD), a protein module that recognizes acetylated lysine residues on histones and other proteins, has recently emerged as a promising therapeutic target for human diseases such as cancer. While most of the studies have been focused on inhibitors against BRDs of the bromo- and extra-terminal domain (BET) family proteins, non-BET family BRD inhibitors remain largely unexplored. Here, we investigated a potential anticancer activity of the recently developed non-BET family BRD inhibitor NVS-CECR2-1 that targets the cat eye syndrome chromosome region, candidate 2 (CECR2). We show that NVS-CECR2-1 inhibits chromatin binding of CECR2 BRD and displaces CECR2 from chromatin within cells. NVS-CECR2-1 exhibits cytotoxic activity against various human cancer cells, killing SW48 colon cancer cells in particular with a submicromolar half maximum inhibition value mainly by inducing apoptosis. The sensitivity of the cancer cells to NVS-CECR2-1 is reduced by CECR2 depletion, suggesting that NVS-CECR2-1 exerts its activity by targeting CECR2. Interestingly, our data show that NVS-CECR2-1 also kills cancer cells by CECR2-independent mechanism. This study reports for the first time the cancer cell cytotoxic activity for NVS-CECR2-1 and provides a possibility of this BRD inhibitor to be developed as an anticancer therapeutic agent.
2020-10-23 | Optimization of Potent ATAD2 and CECR2 Bromodomain Inhibitors with an Atypical Binding Mode.
Most bromodomain inhibitors mimic the interactions of the natural acetylated lysine (KAc) histone substrate through key interactions with conserved asparagine and tyrosine residues within the binding pocket. Herein we report the optimization of a series of phenyl sulfonamides that exhibit a novel mode of binding to non-bromodomain and extra terminal domain (non-BET) bromodomains through displacement of a normally conserved network of four water molecules. Starting from an initial hit molecule, we report its divergent optimization toward the ATPase family AAA domain containing 2 (ATAD2) and cat eye syndrome chromosome region, candidate 2 (CECR2) domains. This work concludes with the identification of (R)-55 (GSK232), a highly selective, cellularly penetrant CECR2 inhibitor with excellent physicochemical properties.
2017-06-13 | GNE-886: A Potent and Selective Inhibitor of the Cat Eye Syndrome Chromosome Region Candidate 2 Bromodomain (CECR2)
The biological function of bromodomains, epigenetic readers of acetylated lysine residues, remains largely unknown. Herein we report our efforts to discover a potent and selective inhibitor of the bromodomain of cat eye syndrome chromosome region candidate 2 (CECR2). Screening of our internal medicinal chemistry collection led to the identification of a pyrrolopyridone chemical lead, and subsequent structure-based drug design led to a potent and selective CECR2 bromodomain inhibitor (GNE-886) suitable for use as an in vitro tool compound.
gene therapies
2025-09-01 | Phenotypic Variability in a Mother and Son with Cat Eye Syndrome
Cat Eye Syndrome (CES) is a rare genomic condition characterized by supernumerary chromosome 22 derivatives or intrachromosomal duplication or triplication. Clinical features vary and include coloboma of the irises, anal atresia, cardiac anomalies, urogenital anomalies, craniofacial anomalies, and varying degrees of developmental delay. The variable expressivity of this condition, combined with its infrequent incidence, makes CES a challenging diagnosis, even among affected members of the same family. In our case, we present a mother and son with non-identical features, and genetic testing revealed a quadruplication in the chromosome 22q11.1q11.21 regions for both individuals. No features of this condition are invariably present, so a high index of clinical suspicion is necessary to make the diagnosis. Recognition of this syndrome and identification of the molecular basis for each individual is essential for appropriate medical management, surveillance, and genetic counseling for affected patients and families.
small molecules
2024-12-23 | The CECR2 bromodomain displays distinct binding modes to select for acetylated histone proteins versus non-histone ligands.
The cat eye syndrome chromosome region candidate 2 (CECR2) protein is an epigenetic regulator involved in chromatin remodeling and transcriptional control. The CECR2 bromodomain (CECR2-BRD) plays a pivotal role in directing the activity of CECR2 through its capacity to recognize and bind acetylated lysine residues on histone proteins. This study elucidates the binding specificity and structural mechanisms of CECR2-BRD interactions with both histone and non-histone ligands, employing techniques such as isothermal titration calorimetry (ITC), nuclear magnetic resonance (NMR) spectroscopy, and a high-throughput peptide assay. The CECR2-BRD selectively binds acetylated histone H3 and H4 ligands, exhibiting a preference for multi-acetylated over mono-acetylated targets. The highest affinity was observed for tetra-acetylated histone H4. Neighboring post-translational modifications, including methylation and phosphorylation, modulate acetyllysine recognition, with significant effects observed for histone H3 ligands. Additionally, this study explored the interaction of the CECR2-BRD with the acetylated RelA subunit of NF-κB, a pivotal transcription factor in inflammatory signaling. Dysregulated NF-κB signaling is implicated in numerous pathologies, including cancer progression, with acetylation of RelA at lysine 310 (K310ac) being critical for its transcriptional activity. Recent evidence linking the CECR2-BRD to RelA suggests it plays a role in inflammatory and metastatic pathways, underscoring the need to understand the molecular basis of this interaction. We found the CECR2-BRD binds to acetylated RelA with micromolar affinity, and uses a distinctive binding mode to recognize this non-histone ligand. These results provide new insight on the role of CECR2 in regulating NF-κB-mediated inflammatory pathways. Functional mutagenesis of critical residues, such as Asn514 and Asp464, highlight their roles in ligand specificity and binding dynamics. Notably, the CECR2-BRD remained monomeric in solution and exhibited differential conformational responses upon ligand binding, suggesting adaptive recognition mechanisms. Furthermore, the CECR2-BRD exclusively interacts with nucleosome substrates containing multi-acetylated histones, emphasizing its role in transcriptional activation within euchromatic regions. These findings position the CECR2-BRD as a key chromatin reader and a promising therapeutic target for modulating transcriptional and inflammatory processes, particularly through the development of selective bromodomain inhibitors.
2022-05-02 | Discovery of a highly potent CECR2 bromodomain inhibitor with 7H-pyrrolo[2,3-d] pyrimidine scaffold.
Cat eye syndrome chromosome region candidate 2 (CECR2) bromodomain is a module of CECR2-containing remodeling factor (CERF), which is a chromatin remodeling complex correlating with transcriptional control and adjustment of chromatin architecture. Potent chemical probes would be beneficial to gain insights into the biochemical and pharmacological functions of CECR2 BRD. Herein, we report the discovery of a series of CECR2 BRD inhibitors with 7H-pyrrolo[2,3-d] pyrimidine scaffold based on molecular docking model of TP-248 and CECR2 BRD. The most potent inhibitor of this series, DC-CBi-22 with IC50 of 8.0 ± 1.4 nM against CECR2 BRD and selectivity over BPTF BRD up to 24.9-fold. The SARs were detailed according to molecular docking. DC-CBi-22 would serve as a useful chemical probe for the study of CECR2.
2021-01-07 | Cytotoxic activity of bromodomain inhibitor NVS-CECR2-1 on human cancer cells.
Bromodomain (BRD), a protein module that recognizes acetylated lysine residues on histones and other proteins, has recently emerged as a promising therapeutic target for human diseases such as cancer. While most of the studies have been focused on inhibitors against BRDs of the bromo- and extra-terminal domain (BET) family proteins, non-BET family BRD inhibitors remain largely unexplored. Here, we investigated a potential anticancer activity of the recently developed non-BET family BRD inhibitor NVS-CECR2-1 that targets the cat eye syndrome chromosome region, candidate 2 (CECR2). We show that NVS-CECR2-1 inhibits chromatin binding of CECR2 BRD and displaces CECR2 from chromatin within cells. NVS-CECR2-1 exhibits cytotoxic activity against various human cancer cells, killing SW48 colon cancer cells in particular with a submicromolar half maximum inhibition value mainly by inducing apoptosis. The sensitivity of the cancer cells to NVS-CECR2-1 is reduced by CECR2 depletion, suggesting that NVS-CECR2-1 exerts its activity by targeting CECR2. Interestingly, our data show that NVS-CECR2-1 also kills cancer cells by CECR2-independent mechanism. This study reports for the first time the cancer cell cytotoxic activity for NVS-CECR2-1 and provides a possibility of this BRD inhibitor to be developed as an anticancer therapeutic agent.
2020-10-23 | Optimization of Potent ATAD2 and CECR2 Bromodomain Inhibitors with an Atypical Binding Mode.
Most bromodomain inhibitors mimic the interactions of the natural acetylated lysine (KAc) histone substrate through key interactions with conserved asparagine and tyrosine residues within the binding pocket. Herein we report the optimization of a series of phenyl sulfonamides that exhibit a novel mode of binding to non-bromodomain and extra terminal domain (non-BET) bromodomains through displacement of a normally conserved network of four water molecules. Starting from an initial hit molecule, we report its divergent optimization toward the ATPase family AAA domain containing 2 (ATAD2) and cat eye syndrome chromosome region, candidate 2 (CECR2) domains. This work concludes with the identification of (R)-55 (GSK232), a highly selective, cellularly penetrant CECR2 inhibitor with excellent physicochemical properties.
2017-06-13 | GNE-886: A Potent and Selective Inhibitor of the Cat Eye Syndrome Chromosome Region Candidate 2 Bromodomain (CECR2)
The biological function of bromodomains, epigenetic readers of acetylated lysine residues, remains largely unknown. Herein we report our efforts to discover a potent and selective inhibitor of the bromodomain of cat eye syndrome chromosome region candidate 2 (CECR2). Screening of our internal medicinal chemistry collection led to the identification of a pyrrolopyridone chemical lead, and subsequent structure-based drug design led to a potent and selective CECR2 bromodomain inhibitor (GNE-886) suitable for use as an in vitro tool compound.
gene therapies
2025-09-01 | Phenotypic Variability in a Mother and Son with Cat Eye Syndrome
Cat Eye Syndrome (CES) is a rare genomic condition characterized by supernumerary chromosome 22 derivatives or intrachromosomal duplication or triplication. Clinical features vary and include coloboma of the irises, anal atresia, cardiac anomalies, urogenital anomalies, craniofacial anomalies, and varying degrees of developmental delay. The variable expressivity of this condition, combined with its infrequent incidence, makes CES a challenging diagnosis, even among affected members of the same family. In our case, we present a mother and son with non-identical features, and genetic testing revealed a quadruplication in the chromosome 22q11.1q11.21 regions for both individuals. No features of this condition are invariably present, so a high index of clinical suspicion is necessary to make the diagnosis. Recognition of this syndrome and identification of the molecular basis for each individual is essential for appropriate medical management, surveillance, and genetic counseling for affected patients and families.
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