RESUMO
Centrosome amplification (CA) is a hallmark of cancer that is strongly associated with highly aggressive disease and worse clinical outcome. Clustering extra centrosomes is a major coping mechanism required for faithful mitosis of cancer cells with CA that would otherwise undergo mitotic catastrophe and cell death. However, its underlying molecular mechanisms have not been fully described. Furthermore, little is known about the processes and players triggering aggressiveness of cells with CA beyond mitosis. Here, we identified Transforming Acidic Coiled-Coil Containing Protein 3 (TACC3) to be overexpressed in tumors with CA, and its high expression is associated with dramatically worse clinical outcome. We demonstrated, for the first time, that TACC3 forms distinct functional interactomes regulating different processes in mitosis and interphase to ensure proliferation and survival of cancer cells with CA. Mitotic TACC3 interacts with the Kinesin Family Member C1 (KIFC1) to cluster extra centrosomes for mitotic progression, and inhibition of this interaction leads to mitotic cell death via multipolar spindle formation. Interphase TACC3 interacts with the nucleosome remodeling and deacetylase (NuRD) complex (HDAC2 and MBD2) in nucleus to inhibit the expression of key tumor suppressors (e.g., p21, p16 and APAF1) driving G1/S progression, and its inhibition blocks these interactions and causes p53-independent G1 arrest and apoptosis. Notably, inducing CA by p53 loss/mutation increases the expression of TACC3 and KIFC1 via FOXM1 and renders cancer cells highly sensitive to TACC3 inhibition. Targeting TACC3 by guide RNAs or small molecule inhibitors strongly inhibits growth of organoids and breast cancer cell line- and patient-derived xenografts with CA by induction of multipolar spindles, mitotic and G1 arrest. Altogether, our results show that TACC3 is a multifunctional driver of highly aggressive breast tumors with CA and that targeting TACC3 is a promising approach to tackle this disease.
Assuntos
Neoplasias da Mama , Fuso Acromático , Humanos , Feminino , Fuso Acromático/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Neoplasias da Mama/patologia , Proteína Supressora de Tumor p53/metabolismo , Centrossomo/metabolismo , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/metabolismoRESUMO
The vicinal diaryl heterocyclic framework has been widely used for the development of compounds with significant bioactivities. In this study, a series of diaryl heterocycles were designed and synthesized based on an in-house diaryl isoxazole derivative (9), and most of the newly synthesized derivatives demonstrated moderate to good antiproliferative activities against a panel of hepatocellular carcinoma and breast cancer cells, exemplified with the diaryl isoxazole 11 and the diaryl pyrazole 85 with IC50 values in the range of 0.7-9.5 µM. Treatments with both 11 and 85 induced apoptosis in these tumor cells, and they displayed antitumor activity in vivo in the Mahlavu hepatocellular carcinoma and the MDA-MB-231 breast cancer xenograft models, indicating that these compounds could be considered as leads for further development of antitumor agents. Important structural features of this compound class for the antitumor activity have also been proposed, which warrant further exploration to guide the design of new and more potent diaryl heterocycles.
RESUMO
INTRODUCTION: The 1,2,3-triazole ring occupies an important space in medicinal chemistry due to its unique structural properties, synthetic versatility and pharmacological potential making it a critical scaffold. Since it is readily available through click chemistry for creating compound collections against various diseases, it has become an emerging area of interest for medicinal chemists. AREAS COVERED: This review article addresses the unique properties of the1,2,3-triazole nucleus as an intriguing ring system in drug discovery while focusing on the most recent medicinal chemistry strategies exploited for the design and development of 1,2,3-triazole analogs as inhibitors of various biological targets. EXPERT OPINION: Evidently, the 1,2,3-triazole ring with unique structural features has enormous potential in drug design against various diseases as a pharmacophore, a bioisoster or a structural platform. The most recent evidence indicates that it may be more emerging in drug molecules in near future along with an increasing understanding of its prominent roles in drug structures. The synthetic feasibility and versatility of triazole chemistry make it certainly ideal for creating compound libraries for more constructive structure-activity relationship studies. However, more comparative and target-specific studies are needed to gain a deeper understanding of the roles of the 1,2,3-triazole ring in molecular recognition.[Figure: see text].
Assuntos
Farmacóforo , Triazóis , Humanos , Triazóis/farmacologia , Triazóis/química , Química Click , Descoberta de Drogas , Química FarmacêuticaRESUMO
In the title compound, C24H20ClNO2, the mean planes of 4-chloro-phenyl, 2-methyl-phenyl and phenyl-ene rings make dihedral angles of 62.8â (2), 65.1â (3) and 15.1â (2)°, respectively, with the 5-methyl-1,2-oxazole ring. In the crystal, mol-ecules are linked by inter-molecular C-Hâ¯N, C-Hâ¯Cl, C-Hâ¯π contacts and π-π stacking inter-actions between the phenyl-ene groups. Hirshfeld surface analysis indicates that the most important contributions to the crystal packing are from Hâ¯H (48.7%), Hâ¯C/Câ¯H (22.2%), Clâ¯H/Hâ¯Cl (8.8%), Hâ¯O/Oâ¯H (8.2%) and Hâ¯N/Nâ¯H (5.1%) inter-actions.
RESUMO
TACC3, a transforming acidic coiled-coil (TACC) family member, is frequently upregulated in a broad spectrum of cancers, including breast cancer. It plays critical roles in protecting microtubule stability and centrosome integrity that is often dysregulated in cancers; therefore, making TACC3 a highly attractive therapeutic target. Here, we identified a new TACC3-targeting chemotype, BO-264, through the screening of in-house compound collection. Direct interaction between BO-264 and TACC3 was validated by using several biochemical methods, including drug affinity responsive target stability, cellular thermal shift assay, and isothermal titration calorimetry. BO-264 demonstrated superior antiproliferative activity to the two currently reported TACC3 inhibitors, especially in aggressive breast cancer subtypes, basal and HER2+, via spindle assembly checkpoint-dependent mitotic arrest, DNA damage, and apoptosis, while the cytotoxicity against normal breast cells was negligible. Furthermore, BO-264 significantly decreased centrosomal TACC3 during both mitosis and interphase. BO-264 displayed potent antiproliferative activity (â¼90% have less than 1 µmol/L GI50 value) in the NCI-60 cell line panel compromising of nine different cancer types. Noteworthy, BO-264 significantly inhibited the growth of cells harboring FGFR3-TACC3 fusion, an oncogenic driver in diverse malignancies. Importantly, its oral administration significantly impaired tumor growth in immunocompromised and immunocompetent breast and colon cancer mouse models, and increased survival without any major toxicity. Finally, TACC3 expression has been identified as strong independent prognostic factor in breast cancer and strongly prognostic in several different cancers. Overall, we identified a novel and highly potent TACC3 inhibitor as a novel potential anticancer agent, inducing spindle abnormalities and mitotic cell death.