Real-world outcomes after discontinuation of covalent BTK inhibitor-based therapy in patients with chronic lymphocytic leukemia/small lymphocytic lymphomaJain, Eyre, Winfree
et alLeuk Lymphoma (2025)
Abstract: This study described real-world treatment patterns and outcomes among patients with CLL/SLL in the post-cBTKi setting. Included were patients who received at least one cBTKi and subsequent line of therapy (LOT) within the Flatiron Health nationwide electronic health record-derived de-identified database (FHD; N = 1,479) and Optum's de-identified Clinformatics® Data Mart Database (CDM; N = 1,020). Frequently observed post-cBTKi treatments in both databases included cBTKi monotherapy (23-30%), anti-CD20 mab monotherapy (∼10%), BCL2i monotherapy (∼9%), BCL2i + anti-CD20 mab (∼9%), cBTKi + BCL2i (∼3%), and cBTKi + anti-CD20 mab (5-7%). From start of immediate LOT following cBTKi discontinuation, median time-to-treatment-discontinuation ranged across databases between 6 and 9 months; median time-to-next-treatment and median overall survival ranged between 18-23 months and 36-57 months, respectively. Observed heterogeneity in treatment patterns and outcomes in two cohorts of patients with CLL/SLL suggests lack of clarity in clinical evidence for treatment choice, and there remains a need for treatment options that deliver improved outcomes in the post-cBTKi setting.
Comprehensive profiling of T-cell exhaustion signatures and establishment of a prognostic model in lung adenocarcinoma through integrated RNA-sequencing analysisZhang, Cheng, Jin
et alTechnol Health Care (2025) 33 (2), 848-862
Abstract: BackgroundT-cell exhaustion (TEX) in the tumor microenvironment causes immunotherapy resistance and poor prognosis.ObjectiveWe used bioinformatics to identify crucial TEX genes associated with the molecular classification and risk stratification of lung adenocarcinoma (LUAD).MethodsBulk RNA sequencing data of patients with LUAD were acquired from open sources. LUAD samples exhibited abnormal TEX gene expression, compared with normal samples. TEX gene-based prognostic signature was established and validated in both TCGA and GSE50081 datasets. Immune correlation and risk group-related functional analyses were also performed.ResultsEight optimized TEX genes were identified using the LASSO algorithm: ERG, BTK, IKZF3, DCC, EML4, MET, LATS2, and LOX. Several crucial Kyoto encyclopedia of genes and genomes (KEGG) pathways were identified, such as T-cell receptor signaling, toll-like receptor signaling, leukocytes trans-endothelial migration, Fcγ R-mediated phagocytosis, and GnRH signaling. Eight TEX gene-based risk score models were established and validated. Patients with high-risk scores had worse prognosis (P < 0.001). A nomogram model comprising three independent clinical factors showed good predictive efficacy for survival rate in patients with LUAD. Correlation analysis revealed that the TEX signature significantly correlated with immune cell infiltration, tumor purity, stromal cells, estimate, and immunophenotype score.ConclusionTEX-derived risk score is a promising and effective prognostic factor that is closely correlated with the immune microenvironment and estimated score. TEX signature may be a useful clinical diagnostic tool for evaluating pre-immune efficacy in patients with LUAD.
Configurational and Conformational Proclivity of an α-Cyanoacrylamide Derivative of IbrutinibWang, Nambiar, Xie
et alJ Org Chem (2025)
Abstract: α-Cyanoacrylamide derivatives of ibrutinib are reversible inhibitors of Bruton's tyrosine kinase (BTK), an important target in B-cell-mediated cancers. We prepared the methyl derivative 1 as part of a larger study and observed interesting complex isomerization behavior that warranted further investigation. Herein, we characterize the solution-state configurational and conformational behavior of 1 by 1D and 2D temperature-dependent NMR and LC-MS. Synthesis of 1 by various routes leads to mixtures of E and Z configurational isomers about its alkene centered at C-31 and C-32. Isomers (E)-1 and (Z)-1 can be separated by reversed-phase HPLC and are stable at room temperature in solution. Interestingly, each configurational isomer undergoes cis/trans conformational isomerization about their respective acrylamide bonds at N-28 with rates dependent on the alkene configuration at C-31. Further, the configurational integrity of the alkene can be compromised at elevated temperatures. Warming pure (E)-1 affords a mixture of E- and Z-isomers resulting in the same relative ratio as observed in the initial synthesis of the compound, with each again exhibiting conformational isomerization about their amide bonds. Warming pure (Z)-1 affords the same results. Knowledge of the isomerization behavior of α-cyanoacrylamides can inform the synthesis, purification, and utility of this class of molecules.
Macrocyclic Rearrangement Ion Fragmentation of Glutathione Conjugates of Cyclobutane-Containing Covalent BTK InhibitorsMuste, Gu, Vandeveer
et alJ Am Soc Mass Spectrom (2025)
Abstract: Covalent BTK-inhibitor drugs often contain reactive acrylamide warheads designed to irreversibly bind to their protein targets at free thiol cysteines in the kinase active site. This reactivity also makes covalent inhibitors susceptible to conjugation to endogenous tripeptide glutathione (GSH), leading to clearance. During lead optimization efforts for the drug discovery of covalent BTK inhibitor BIIB129, some expected GSH adducts resulted in an unexpected and highly abundant rearrangement fragment ion in LC-MS/MS. By examining more than 30 inhibitors, the rearrangements were found to be dependent on the presence of a cycloalkane linker that connects the warhead to the kinase hinge binder motif of drug molecules. The proposed mechanism includes the formation of a 16-membered macrocyclic intermediate between the γ-glutamic acid residue (Glu) of GSH and a methyl-cyclobutyl cation, resulting in a rearrangement fragment originating from two distant parts of the adduct molecule separated by the warhead conjugated with the cysteine residue in between. Rich sets of chemical analogues available during the lead optimization enabled confirmation of the macrocyclic rearrangement. Proposed macrocyclic rearrangement was verified using GSH derivatives: N-acetylation of the γ-Glu blocked the rearrangement, and esterification of the γ-Glu side chain resulted in an expected shift in the mass of rearranged fragment ion. Proposed rearranged ion structures were supported by MS3 and MS4 fragmentations. Comparisons of the ion fragmentation of GSH conjugates between cis and trans matched pairs suggest a concerted mechanism for the cyclobutane linker and a stepwise mechanism for the methylcyclobutane linker, respectively.
膜杰作
Star Staining
