ACS Pharmacology and Translational Science最新文献

Hematological cancers, such as lymphomas and leukemias, pose significant challenges in oncology, necessitating a deeper understanding of their molecular landscape to enhance therapeutic strategies. This article critically examines and discusses recent research on the roles of G protein-coupled receptors (GPCRs) in myeloma, lymphomas, and leukemias with a particular focus on pediatric acute lymphoblastic (lymphocytic) leukemia (ALL). By utilizing RNA sequencing (RNA-seq), we analyzed GPCR expression patterns in pediatric ALL samples (aged 3-12 years old), with a further focus on Class A orphan GPCRs. Our analysis revealed distinct GPCR expression profiles in pediatric ALL, identifying several candidates with aberrant upregulated expression compared with healthy counterparts. Among these GPCRs, GPR85, GPR65, and GPR183 have varying numbers of studies in the field of hematological cancers and pediatric ALL. Furthermore, we explored missense mutations of pediatric ALL in relation to the RNA gene expression findings, providing insights into the genetic underpinnings of this disease. By integrating both RNA-seq and missense mutation data, this article aims to provide an insightful and broader perspective on the potential correlations between specific GPCR and their roles in pediatric ALL.

For the prevention of SARS-CoV-2 infection, four Fv-antibodies with binding affinity for the ACE2 receptor were screened from an Fv-antibody library. The screened Fv-antibodies were expressed as soluble proteins and estimated to have a high binding affinity, comparable to that between SARS-CoV-2 and the ACE2 receptor. The interaction between the Fv-antibodies and the ACE2 receptor was analyzed using docking simulation, and the significant binding affinity of the screened Fv-antibodies was attributed to the homology in amino acid sequence with the ACE2 receptor. The neutralizing activities of the Fv-antibodies were demonstrated using a cell-based infection assay based on four pseudo-virus types with SARS-CoV-2 variant spike proteins (Wild-type D614, Delta B.1.617.2, and Omicron BA.2, and Omicron BA.4/5).

The human protein kinase CK2 is a promising target for cancer treatment. Only two CK2 inhibitors have reached clinical trials until today. Among others, a dibenzofuran scaffold has emerged as highly prospective for the development of new CK2 inhibitors. Thirty-three newly synthesized dibenzofuran-based compounds were tested on their inhibitory potential in vitro. 7,9-Dichloro-8-hydroxy-4-[(phenylamino)methylene]-1,2-dihydro-dibenzo[b,d]furan-3(4H)-one (12b) and 7,9-dibromo-8-hydroxy-4-[(phenylamino)methylene]-1,2-dihydro-dibenzo[b,d]furan-3(4H)-one (12c) showed the lowest IC₅₀ values with 5.8 nM for both. The dibenzofuran-based CK2 inhibitors crossed the cell membrane of LNCaP human prostate carcinoma cells and reduced intracellular CK2 activity. Among 70 kinases from different representative subgroups of the human kinome, CK2 was most strongly inhibited by compound 12c. Co-crystallization of 12c together with CK2α indicated a π-halogen bond of the bromine at position C9 with the gatekeeper amino acid Phe113. CK2α could bind both the E- and Z-isomers of 12c. Our results provide new insights into the structure-activity relationships of dibenzofuran derivatives.

The human protein kinase CK2 is a promising target for cancer treatment. Only two CK2 inhibitors have reached clinical trials until today. Among others, a dibenzofuran scaffold has emerged as highly prospective for the development of new CK2 inhibitors. Thirty-three newly synthesized dibenzofuran-based compounds were tested on their inhibitory potential in vitro. 7,9-Dichloro-8-hydroxy-4-[(phenylamino)methylene]-1,2-dihydro-dibenzo[b,d]furan-3(4H)-one (12b) and 7,9-dibromo-8-hydroxy-4-[(phenylamino)methylene]-1,2-dihydro-dibenzo[b,d]furan-3(4H)-one (12c) showed the lowest IC₅₀ values with 5.8 nM for both. The dibenzofuran-based CK2 inhibitors crossed the cell membrane of LNCaP human prostate carcinoma cells and reduced intracellular CK2 activity. Among 70 kinases from different representative subgroups of the human kinome, CK2 was most strongly inhibited by compound 12c. Co-crystallization of 12c together with CK2α indicated a π-halogen bond of the bromine at position C9 with the gatekeeper amino acid Phe113. CK2α could bind both the E- and Z-isomers of 12c. Our results provide new insights into the structure–activity relationships of dibenzofuran derivatives.

For the prevention of SARS-CoV-2 infection, four Fv-antibodies with binding affinity for the ACE2 receptor were screened from an Fv-antibody library. The screened Fv-antibodies were expressed as soluble proteins and estimated to have a high binding affinity, comparable to that between SARS-CoV-2 and the ACE2 receptor. The interaction between the Fv-antibodies and the ACE2 receptor was analyzed using docking simulation, and the significant binding affinity of the screened Fv-antibodies was attributed to the homology in amino acid sequence with the ACE2 receptor. The neutralizing activities of the Fv-antibodies were demonstrated using a cell-based infection assay based on four pseudo-virus types with SARS-CoV-2 variant spike proteins (Wild-type D614, Delta B.1.617.2, and Omicron BA.2, and Omicron BA.4/5).

The tumor suppressor p53 is frequently mutated in human cancers. The Y220C mutant is the ninth most common p53 cancer mutant and is classified as a structural mutant, as it leads to strong thermal destabilization and degradation by creating a solvent-accessible hydrophobic cleft. To identify small molecules that thermally stabilize p53, we employed DSF to screen S_NAr-type electrophiles from our covalent fragment library (CovLib) for binding to different structural (Y220C, R282W) and DNA contact (R273H) mutants of p53. The reactive fragments SN001, SN006, and SN007 were detected to specifically stabilize Y220C, indicating the arylation of Cys220 in the mutational cleft, as confirmed by X-ray crystallography. The fragments occupy the central cavity and mimic the ring system of the WT tyrosine lost by the mutation. Surpassing previously reported noncovalent ligands, SN001 stabilized T-p53C-Y220C concentration-dependently up to 4.45 °C and, due to its small size, represents a promising starting point for optimization.

The tumor suppressor p53 is frequently mutated in human cancers. The Y220C mutant is the ninth most common p53 cancer mutant and is classified as a structural mutant, as it leads to strong thermal destabilization and degradation by creating a solvent-accessible hydrophobic cleft. To identify small molecules that thermally stabilize p53, we employed DSF to screen S_NAr-type electrophiles from our covalent fragment library (CovLib) for binding to different structural (Y220C, R282W) and DNA contact (R273H) mutants of p53. The reactive fragments SN001, SN006, and SN007 were detected to specifically stabilize Y220C, indicating the arylation of Cys220 in the mutational cleft, as confirmed by X-ray crystallography. The fragments occupy the central cavity and mimic the ring system of the WT tyrosine lost by the mutation. Surpassing previously reported noncovalent ligands, SN001 stabilized T-p53C-Y220C concentration-dependently up to 4.45 °C and, due to its small size, represents a promising starting point for optimization.

Although small-molecule inhibitors with moderate efficacy targeting MYC have been previously described, to this point, research efforts have failed to bring a suitable small-molecule MYC inhibitor to the clinic. Herein, the discovery of a series of novel MYC degraders bearing VHL to target the "undruggable" MYC is presented. The molecules are based on connecting a known MYC binder to a VHL ligand or pomalidomide to induce MYC degradation in various cancer cells known to express MYC. Representative compounds from our work induced MYC degradation in a time- and dose-dependent manner. Selected compounds, CSI86 and CSI107, displayed antiproliferative activity (IC₅₀ values of 13-18 μM) against breast and prostate cancer cells. The lead molecules were further evaluated in terms of cell uptake, potential to degrade MYC, and pharmacokinetics in mice. Encouraging results presented herein suggest that the presented analogs may serve as prototype structures of future therapeutic agents for the treatment of MYC-dependent tumors. MYC protein degraders can well complement the more established inhibition approaches that have been presented in the past (e.g., disruption of the MYC-MAX complex formation by small-molecule inhibitors).

Although small-molecule inhibitors with moderate efficacy targeting MYC have been previously described, to this point, research efforts have failed to bring a suitable small-molecule MYC inhibitor to the clinic. Herein, the discovery of a series of novel MYC degraders bearing VHL to target the “undruggable” MYC is presented. The molecules are based on connecting a known MYC binder to a VHL ligand or pomalidomide to induce MYC degradation in various cancer cells known to express MYC. Representative compounds from our work induced MYC degradation in a time- and dose-dependent manner. Selected compounds, CSI86 and CSI107, displayed antiproliferative activity (IC₅₀ values of 13–18 μM) against breast and prostate cancer cells. The lead molecules were further evaluated in terms of cell uptake, potential to degrade MYC, and pharmacokinetics in mice. Encouraging results presented herein suggest that the presented analogs may serve as prototype structures of future therapeutic agents for the treatment of MYC-dependent tumors. MYC protein degraders can well complement the more established inhibition approaches that have been presented in the past (e.g., disruption of the MYC–MAX complex formation by small-molecule inhibitors).

Breast cancer with positive expression of estrogen receptor α (ERα+) accounts for 70% of breast cancer cases, whose predominant treatment is currently endocrine therapy. The main strategy of endocrine therapy for ERα+ breast cancer is to inhibit the ERα signaling pathway and downregulate ERα levels, which often results in mutations in the ligand-binding domain (LBD) of ERα, leading to significant resistance to subsequent treatment in patients. To combat drug resistance, we first proposed a novel aptamer PROTAC strategy through specifically targeted degradation of ERα via targeting the DNA-binding domain (DBD) of ERα. We proved that this strategy is capable of targeting ERα for degradation through ubiquitination, leading to the inhibition of proliferation in ERα+ breast cancer cells and tamoxifen-resistant breast cancer cells. Furthermore, we investigated the mechanisms involved in overcoming resistance. By circumventing drug resistance associated with LBD mutations in ERα, our approach provides a promising avenue for the discovery of new therapeutic agents.