RESUMEN
BACKGROUND: Catenin (Cadherin-Associated Protein), Beta 1 (CTNNB1) genomic alterations are rare in prostate cancer (PCa). Gain-of-function mutations lead to overexpression of ß-catenin, with consequent hyperactivation of the Wnt/ß-catenin signaling pathway, implicated in PCa progression and treatment resistance. To date, successful targeted treatment options for Wnt/ß-catenin - driven PCa are lacking. METHODS: We report a rare histologic transformation of a CTNNB1 (ß-catenin) mutated metastatic castration resistant prostate cancer (mCRPC), clinically characterized by highly aggressive disease course. We histologically and molecularly characterized the liver metastatic tumor samples, as well as successfully generated patient-derived organoids (PDOs) and patient-derived xenograft (PDX) from a liver metastasis. We used the generated cell models for further molecular characterization and drug response assays. RESULTS: Immunohistochemistry of liver metastatic biopsies and PDX tumor showed lack of expression of typical PCa (e.g., AR, PSA, PSAP, ERG) or neuroendocrine markers (synaptophysin), compatible with double-negative CRPC, but was positive for nuclear ß-catenin expression, keratin 7 and 34ßE12. ERG rearrangement was confirmed by fluorescent in situ hybridization (FISH). Drug response assays confirmed, in line with the clinical disease course, lack of sensitivity to common drugs used in mCRPC (e.g., enzalutamide, docetaxel). The casein kinase 1 (CK1) inhibitor IC261 and the tankyrase 1/2 inhibitor G700-LK showed modest activity. Moreover, despite harbouring a CTNNB1 mutation, PDOs were largely insensitive to SMARCA2/4- targeting PROTAC degraders and inhibitor. CONCLUSIONS: The reported CTNNB1-mutated mCRPC case highlights the potential challenges of double-negative CRPC diagnosis and underlines the relevance of further translational research to enable successful targeted treatment of rare molecular subtypes of mCRPC.
Asunto(s)
Mutación , beta Catenina , Humanos , Masculino , beta Catenina/genética , beta Catenina/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/patología , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/patología , Animales , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Anciano , Progresión de la EnfermedadRESUMEN
Casein kinase (CK) is a type of conserved serine/threonine protein kinase that phosphorylates many important proteins in body. Researchers found that CK is involved in a variety of signaling pathways, and also plays an important role in inflammation, cancer, and nervous system diseases. Thus, it is considered to be a promising target for the treatment of related diseases. Many CK small molecule inhibitors have been reported so far, and most are ATP competitive inhibitors. However, these CK inhibitors lack the basic properties required for in vivo use, such as selectivity, cell permeability, metabolic stability, correct pharmacokinetic characteristics, and cellular environment. But small molecule inhibitors still have an advantage in drug research due to their controllable pharmacological and pharmacokinetic properties. CX-4945 discovered by Cylene Pharmaceutical is the only one CK2 inhibitor entering into Phase II clinical trials till now. In recent years, significant advances have been made in the design of non-competitive inhibitors of CK and in the application of multi-target inhibition strategies. Here, we review the published CK inhibitors and analyze their structure-activity relationships (SAR). We also summarized the eutectic structure with identified hot spots to provide a reference for future drug discovery.
Asunto(s)
Quinasa de la Caseína II/antagonistas & inhibidores , Quinasa de la Caseína I/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Animales , Quinasa de la Caseína I/química , Quinasa de la Caseína I/metabolismo , Quinasa de la Caseína II/química , Quinasa de la Caseína II/metabolismo , Descubrimiento de Drogas , Humanos , Simulación del Acoplamiento MolecularRESUMEN
The reference standards methyl 3-((2,2-difluoro-5H-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]imidazol-6-yl)carbamoyl)benzoate (5a) and N-(2,2-difluoro-5H-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]imidazol-6-yl)-3-methoxybenzamide (5c), and their corresponding desmethylated precursors 3-((2,2-difluoro-5H-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]imidazol-6-yl)carbamoyl)benzoic acid (6a) and N-(2,2-difluoro-5H-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]imidazol-6-yl)-3-hydroxybenzamide (6b), were synthesized from 5-amino-2,2-difluoro-1,3-benzodioxole and 3-substituted benzoic acids in 5 and 6 steps with 33% and 11%, 30% and 7% overall chemical yield, respectively. Carbon-11-labeled casein kinase 1 (CK1) inhibitors, [11C]methyl 3-((2,2-difluoro-5H-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]imidazol-6-yl)carbamoyl)benzoate ([11C]5a) and N-(2,2-difluoro-5H-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]imidazol-6-yl)-3-[11C]methoxybenzamide ([11C]5c), were prepared from their O-desmethylated precursor 6a or 6b with [11C]CH3OTf through O-[11C]methylation and isolated by HPLC combined with SPE in 40-45% radiochemical yield, based on [11C]CO2 and decay corrected to end of bombardment (EOB). The radiochemical purity was >99%, and the molar activity (MA) at EOB was 370-740â¯GBq/µmol with a total synthesis time of â¼40-min from EOB.