B-cell Lymphoma-2 Inhibitor Research Articles

Improving Treatment Options for Patients with Double Refractory CLL

The proliferation and survival of chronic lymphocytic leukemia (CLL) cells are heavily dependent on B-cell receptor (BCR) signaling and resistance to apoptosis. Approvals of multiple covalent Bruton’s tyrosine kinas inhibitors (cBTKis) as well as the B-cell lymphoma-2 inhibitor (BCL2i) venetoclax targeting these pathways have revolutionized the treatment of CLL and small lymphocytic lymphoma (SLL). The superiority of these treatments over chemoimmunotherapy has been proven in phase III studies in both treatment-naïve and relapsed refractory settings, leading to the majority of patients with CLL being treated sequentially with cBTKis and the BCL2i venetoclax as their first- and second-line therapies. While most patients with CLL respond for many years to these sequenced treatments, they are unfortunately not curative. There remains an unmet need for effective treatment options for patients who progressed after treatment with both cBTKis and BCL2i, also referred to as double refractory patients. Treatment options for double refractory CLL has improved recently with the approval of the non-covalent BTK inhibitor (ncBTKi) pirtobrutinib as well as the CD19 targeted chimeric antigen receptor T-cell (CAR T-cell) therapy lisocabtagene maraleucel (liso-cel). These recently approved treatment options for patients with CLL with at least two prior lines of therapy have fortunately demonstrated efficacy for double refractory CLL. Additionally, there are several novel treatment options in clinical development, including bi-specific antibodies, second-generation BCL2is, new ncBTKis, and BTK degraders. Understanding resistance mechanisms to existing cBTKis and venetoclax can potentially inform us of the best utilization of available treatment options for double refractory CLL and provide a personalized approach for these patients. In this review, a challenging example of a double refractory patient with CLL will serve as the basis for a review of available literature on the treatment of double refractory CLL/SLL.

Resveratrol as a BCL6 natural inhibitor suppresses germinal center derived Non-Hodgkin lymphoma cells growth.

Non-Hodgkin lymphomas (NHL), including diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), and follicular lymphoma (FL), predominantly arise from B cells undergoing germinal center (GC) reactions. The transcriptional repressor B-cell lymphoma 6 (BCL6) is indispensable for GC formation and contributes to lymphomagenesis via its BTB domain-mediated suppression of target genes. Dysregulation of BCL6 underpins the pathogenesis of GC-derived NHL. While pharmacological targeting the BCL6-BTB domain has shown therapeutic promise, natural product-based inhibitors remain underexplored. In this study, resveratrol, a polyphenolic compound derived from grapes, was identified as a potent BCL6 inhibitor through a comprehensive screen of traditional Chinese medicine monomers using Homogeneous Time-Resolved Fluorescence (HTRF) assay. As a BCL6 natural inhibitor, resveratrol effectively disrupted the BCL6/SMRT interaction, reactivated suppressed gene expression, and inhibited the proliferation of GC-derived NHL cells. It also exhibited synergistic efficacy when combined with EZH2 and PRMT5 inhibitors. In vivo, resveratrol suppressed GC formation, reduced follicular helper T-cell frequencies, impaired class-switch recombination, and disrupted immunoglobulin affinity maturation. Furthermore, it markedly inhibited the progression of GC-derived NHL in animal models. Our findings demonstrate that resveratrol functions as a natural BCL6 inhibitor with significant therapeutic potential for the treatment of GC-derived NHL.

Integrating machine learning and structural dynamics to explore B-cell lymphoma-2 inhibitors for chronic lymphocytic leukemia therapy.

Chronic lymphocytic leukemia (CLL) is a malignancy caused by the overexpression of the anti-apoptotic protein B-cell lymphoma-2 (BCL-2), making it a critical therapeutic target. This study integrates computational screening, molecular docking, and molecular dynamics to identify and validate novel BCL-2 inhibitors from the ChEMBL database. Starting with 836 BCL-2 inhibitors, we performed ADME and Lipinski's Rule of Five (RO5) filtering, clustering, maximum common substructure (MCS) analysis, and machine learning models (Random Forest, SVM, and ANN), yielding a refined set of 124 compounds. Among these, 13 compounds within the most common substructure (MCS1) cluster showed promising features and were prioritized. A docking-based re-evaluation highlighted four lead compounds-ChEMBL464268, ChEMBL480009, ChEMBL464440, and ChEMBL518858-exhibiting notable binding affinities. Although a reference molecule outperformed in docking, molecular dynamics (MD), and binding energy analyses, it failed ADME and Lipinski criteria, unlike the selected leads. Further validation through MD simulations and MM/GBSA energy calculations confirmed stable binding interactions for the leads, with ChEMBL464268 showing the highest stability and binding affinity (ΔGtotal = -80.35 ± 11.51kcal/mol). Free energy landscape (FEL) analysis revealed stable energy minima for these complexes, underscoring conformational stability. Despite moderate activity (pIC₅₀ values from 4.3 to 5.82), the favorable pharmacokinetic profiles of these compounds position them as promising BCL-2 inhibitor leads, with ChEMBL464268 emerging as the most promising candidate for further CLL therapeutic development.

LP-118 is a novel B-cell lymphoma 2 / extra-large inhibitor that demonstrates efficacy in models of venetoclaxresistant chronic lymphocytic leukemia.

Patients with chronic lymphocytic leukemia (CLL) respond well to initial treatment with the B-cell lymphoma 2 (BCL2) inhibitor venetoclax. Upon relapse, they often retain sensitivity to BCL2 targeting, but durability of response remains a concern. We hypothesize that targeting both BCL2 and B-cell lymphoma-extra large (BCLXL) will be a successful strategy to treat CLL, including for patients who relapse on venetoclax. To test this hypothesis, we conducted a pre-clinical investigation of LP-118, a highly potent inhibitor of BCL2 with moderate BCLXL inhibition to minimize platelet toxicity. This study demonstrated that LP-118 induces efficient BAK activation, cytochrome C release, and apoptosis in both venetoclax-naïve and -resistant CLL cells. Significantly, LP-118 is effective in cell lines expressing the BCL2 G101V mutation and in cells expressing BCLXL but lacking BCL2 dependence. Using an immunocompetent mouse model, Eμ-TCL1, LP-118 demonstrates low platelet toxicity, which hampered earlier BCLXL inhibitors. Finally, LP-118 in the RS4;11 and OSU-CLL xenograft models results in decreases in tumor burden and survival advantage, respectively. These results provide a mechanistic rationale for the evaluation of LP-118 for the treatment of venetoclax-responsive and -relapsed CLL.

Interindividual variability in CYP3A-mediated venetoclax metabolism invitro and invivo in patients with chronic lymphocytic leukemia.

Venetoclax is a first-in-class orally administered B-cell lymphoma-2 inhibitor used to treat chronic lymphocytic leukemia (CLL). Venetoclax is primarily metabolized in the liver by cytochrome P450 (CYP) 3A4 to its major metabolite M27, via M5, and M2, M3, and M4 via oxidation. Although venetoclax is a breakthrough in CLL treatment, managing drug safety and toxicity remains a clinical challenge. The objectives of this study were to investigate how individual CYP3A activity and protein expression affect hepatic venetoclax metabolism invitro and examine whether plasma 4β-hydroxycholesterol (4β-HC)/cholesterol ratio can predict venetoclax metabolism invitro and invivo. In human liver microsomes (n = 20) and primary human hepatocytes (n = 15), venetoclax metabolite formation varied widely between donors and significantly correlated with CYP3A activity (midazolam 1'-hydroxylation) and CYP3A4 protein expression. Venetoclax metabolite formation positively correlated with 4β-HC/cholesterol ratio in plasma samples from the matched non-infant donors (n = 14, ages 3-63 years). In an observational pilot study of real-world patients with CLL (n = 12, ages 56-84 years) treated with venetoclax, the plasma M3/venetoclax metabolic ratio negatively correlated with plasma 4β-HC/cholesterol ratio and positively correlated with patient age. Plasma 4β-HC/cholesterol ratio negatively correlated with patient age. Differences between the invitro data, which showed a positive association between venetoclax metabolism, hepatic CYP3A markers, and plasma 4β-HC/cholesterol ratio, and the invivo findings in patients with CLL could be due to age or other factors regulating plasma 4β-HC/cholesterol and/or venetoclax disposition. Future studies with larger sample sizes are needed to investigate age-related changes in venetoclax metabolism and plasma 4β-HC/cholesterol ratio.

Chidamide and venetoclax synergistically regulate the Wnt/β-catenin pathway by MYCN/DKK3 in B-ALL.

B-cell acute lymphocytic leukemia (B-ALL) is a malignant proliferative B-lymphocyte disease. Although the outcome of B-ALL has greatly improved with combined chemotherapy, immunotherapy, and hematopoietic stem cell transplantation, some patients still experience drug resistance, relapse and a low long-term survival rate, therefore, finding novel approaches to improve the outcome of adult B-ALL patients is critical. Our previous studies revealed that the selective histone deacetylase inhibitor (HDACi) chidamide can inhibit the Wnt/β-catenin signaling pathway by inhibiting MYCN and increasing the expression of DKK3 in B-ALL cells. Some studies have indicated that histone deacetylase inhibitors (HDACis) can dysregulate the B-cell lymphoma-2 (BCL2) protein family, we speculate that chidamide and BCL2 inhibitor venetoclax synergistically inhibit the Wnt/β-catenin signaling pathway by inhibiting MYCN expression and increasing DKK3 expression. In our study, the in vitro and in vivo experiments confirmed that chidamide and venetoclax synergistically inhibited the expression of MYCN and increased the expression of DKK3 by inhibiting the activity of HDAC and BCL2, inhibiting the Wnt/β-catenin signaling pathway and B-ALL cell proliferation. These findings indicate that the HDACi chidamide and the BCL2 inhibitor venetoclax can be used in combination to treat B-ALL, providing a new method and strategy for treating B-ALL.

Discovery of novel azo pyrimidinone derivatives as B-cell lymphoma-2 inhibitors with potential antineoplastic activity: Synthesis, characterization, in-silico, and in-vitro studies

In the present investigation, novel azo compounds containing pyrimidinone moiety incorporated with different heterocycles were synthesized and characterized using spectroscopic techniques including FT-IR, 1H-NMR, 13C-NMR, and elemental analysis. These azo derivatives were assessed in- silico to determine how well they could inhibit the antiapoptotic B-cell lymphoma-2 (Bcl-2) protein while providing information about their pharmacokinetic characteristics. Our results elucidated that the majority of these new compounds demonstrated moderate to strong binding energies against Bcl-2 target protein comparable to that of venetoclax FDA-approved Bcl-2 inhibitor. Compound 4 showed the top-ranked binding energy followed by compound 5 and compound 3 with values equal to -11.65, -9.53, and -7.82 kcal/mol respectively, while compounds 6 and 7 showed moderate binding energies compared with venetoclax drug that give binding energy equal to -6.95 kcal/mol Furthermore, the in-vitro investigations observed that compounds 4, 5 and 3 demonstrated superior anticancer efficacy against HepG2 and MCF-7 compared to venetoclax drug that gives IC50 equal to 5.10±0.54 and 4.17±0.8 μM respectively. Moreover, all newly synthesized compounds had no cytotoxic impact on WI-38 normal cells contrary to venetoclax drug (26.72±0.94 μM) which was confirmed also through ADMES drug-likeness scores study. Additionally, compounds 4, 5, and 3 revealed an efficient antioxidant scavenging capacity towards DPPH free radicals while compounds 6 and 7 showed a weak scavenging effect compared with standard L. ascorbic acid. Ultimately, the newly synthesized pyrimidinone compounds 4, 5, and 3 that were examined showed encouraging apoptotic and antiproliferative properties. Further, in upcoming clinical studies, the newly synthesized pyrimidinone compounds may prove to be effective anticancer medicines.

The Anti-Leukemic Activities of Campesterol and Α-Tocopherol Against BCL-2 Target through Computational Drug Design Approaches.

Heterogeneous Acute Myeloid Leukemia (AML) causes substantial worldwide morbidity and death. AML is characterized by excessive proliferation of immature myeloid cells in the bone marrow and impaired apoptotic regulator expression. B-Cell Lymphoma 2 (BCL-2), an anti-apoptotic protein overexpressed in AML, promotes leukemic cell survival and chemoresistance. Thus, reducing BCL-2 may treat AML. Anticancer activities are found in Aloe barbadensis Miller (Aloe vera). Thus, this work used molecular modeling to assess Aloe vera bioactive chemicals as BCL-2 inhibitors. Molecular docking simulation showed that all identified Aloe vera phytocompounds have strong BCL-2 binding affinities (-6.7 to -8.7 kcal/mol). Campesterol and α-tocopherol were identified as promising compounds for BCL-2 inhibitor research based on their drug-likeness, pharmacokinetics, and toxicity profiles. The stability and conformational of the BCL-2-compound complexes showed that the compounds were stable in BCL-2's binding pocket. Campesterol and α-tocopherol are promising BCL-2 inhibitors that might become effective anti-leukemic therapies with additional in vitro and in vivo research.

B Cell Lymphoma 6 (BCL6): A Conserved Regulator of Immunity and Beyond.

B cell lymphoma 6 (BCL6) is a conserved multi-domain protein that functions principally as a transcriptional repressor. This protein regulates many pivotal aspects of immune cell development and function. BCL6 is critical for germinal center (GC) formation and the development of high-affinity antibodies, with key roles in the generation and function of GC B cells, follicular helper T (Tfh) cells, follicular regulatory T (Tfr) cells, and various immune memory cells. BCL6 also controls macrophage production and function as well as performing a myriad of additional roles outside of the immune system. Many of these regulatory functions are conserved throughout evolution. The BCL6 gene is also important in human oncology, particularly in diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL), but also extending to many in other cancers, including a unique role in resistance to a variety of therapies, which collectively make BCL6 inhibitors highly sought-after.

NL101 synergizes with the BCL-2 inhibitor venetoclax through PI3K-dependent suppression of c-Myc in acute myeloid leukaemia

BackgroundAcute myeloid leukaemia (AML) comprises a group of heterogeneous and aggressive haematological malignancies with unsatisfactory prognoses and limited treatment options. Treatments targeting B-cell lymphoma-2 (BCL-2) with venetoclax have been approved for patients with AML, and venetoclax-based drug combinations are becoming the standard of care for older patients unfit for intensive chemotherapy. However, the therapeutic duration of either single or combination strategies is limited, and the development of resistance seems inevitable. Therefore, more effective combination regimens are urgently needed.MethodsThe efficacy of combination therapy with NL101, a SAHA-bendamustine hybrid, and venetoclax was evaluated in preclinical models of AML including established cell lines, primary blasts from patients, and animal models. RNA-sequencing and immunoblotting were used to explore the underlying mechanism.ResultsNL101 significantly potentiated the activity of venetoclax in AML cell lines, as evidenced by the enhanced decrease in viability and induction of apoptosis. Mechanistically, the addition of NL101 to venetoclax decreased the stability of the antiapoptotic protein myeloid cell leukaemia-1 (MCL-1) by inhibiting ERK, thereby facilitating the release of BIM and triggering mitochondrial apoptosis. Moreover, the strong synergy between NL101 and venetoclax also relied on the downregulation of c-Myc via PI3K/Akt/GSK3β signalling. The combination of NL101 and venetoclax synergistically eliminated primary blasts from 10 AML patients and reduced the leukaemia burden in an MV4-11 cell-derived xenograft model.ConclusionsOur results encourage the pursuit of clinical trials of combined treatment with NL101 and venetoclax and provide a novel venetoclax-incorporating therapeutic strategy for AML.

Glutaminase 1 plays critical roles in myelodysplastic syndrome and acute myeloid leukemia cells.

Myelodysplastic syndrome (MDS) features bone marrow failure and a heightened risk of evolving into acute myeloid leukemia (AML), increasing with age and reducing overall survival. Given the unfavorable outcomes of MDS, alternative treatments are necessary. Glutamine, the most abundant amino acid in the blood, is metabolized first by the enzyme glutaminase (GLS). To investigate whether GLS is involved in the progression of MDS. The efficacy of GLS inhibitors (CB839 or IPN60090) and BCL2 inhibitor venetoclax was also examined. We employed GLS inhibitors (CB839, IPN60090) and the BCL2 inhibitor venetoclax, prepared as detailed. MDS and AML cell lines were cultured under standard and modified (hypoxic, glutamine-free) conditions. Viability, proliferation, and caspase activity were assessed with commercial kits. RT-PCR quantified gene expression post-shRNA transfection. Mitochondrial potential, ATP levels, proteasome activity, and metabolic functions were evaluated using specific assays. Statistical analyses (t-tests, ANOVA) validated the findings. The glutamine-free medium inhibited the growth of MDS cells. GLS1 expression was higher in AML cells than in normal control samples (GSE15061), whereas GLS2 expression was not. Treatment of MDS and AML cells for 72 h was inhibited in a dose-dependent manner by GLS inhibitors. Co-treatment with the B-cell lymphoma 2 (BCL2) inhibitor venetoclax and GLS inhibitors increased potency. Cells transfected with GLS1 short hairpin RNA showed suppressed proliferation under hypoxic conditions and increased sensitivity to venetoclax. Targeting glutaminolysis and BCL2 inhibition enhances the therapeutic efficacy and has been proposed as a novel strategy for treating high-risk MDS and AML.

IL-17A exacerbates corpus cavernosum fibrosis and neurogenic erectile dysfunction by inducing CSMC senescence via the mTORC2-ACACA pathway

BackgroundNeurogenic erectile dysfunction, characterized by neurological repair disorders and progressive corpus cavernosum fibrosis (CCF), is an unbearable disease with limited treatment success. IL-17A exhibits a complex role in tissue remodelling. Nevertheless, the precise role and underlying mechanisms of IL-17A in CCF under denervation remain unclear.MethodsPCR array was employed to identified differentially expressed genes between neurogenic ED and normal rats. IL-17A expression and its main target cells were analyzed using Western blotting, immunofluorescence and immunohistochemistry. The phenotypic regulation of IL-17A on corpus cavernosum smooth muscle cells (CSMCs) was evaluated by cell cycle experiments and SA-β-Gal staining. The mechanism of IL-17A was elucidated using non-target metabolomics and siRNA technique. Finally, IL-17A antagonist and ABT-263 (an inhibitor of B-cell lymphoma 2/w/xL) were utilized to enhance the therapeutic effect in a rat model of neurogenic ED.ResultsIL-17A emerged as the most significantly upregulated gene in the corpus cavernosum of model rats. It augmented the senescence transformation and fibrotic response of CSMCs, and exhibited a strong correlation with CCF. Mechanistically, IL-17A facilitated CCF by activating the mTORC2-ACACA signalling pathway, upregulating of CSMCs lipid synthesis and senescence transition, and increasing the secretion of fibro-matrix proteins. In vivo, the blockade of IL-17A-senescence signalling improved erectile function and alleviated CCF in neurogenic ED.ConclusionsIL-17A assumes a pivotal role in denervated CCF by activating the mTORC2-ACACA signalling pathway, presenting itself as a potential therapeutic target for effectively overcoming CCF and erection rehabilitation in neurogenic ED.Graphical abstractIL-17A is significantly upregulated in the corpus cavernosum under denervated conditions, promoting the senescence transformation and fibrotic response of corpus cavernosum smooth muscle cells, primarily through the activation of the mTORC2-ACACA signalling pathway. Blocking the IL-17A-senescence signalling axis can improve erectile function and alleviate corpus cavernosum fibrosis, suggesting that this pathway represents a potential therapeutic target for neurogenic erectile dysfunction.

Discovery of novel BCL6-Targeting PROTACs with effective antitumor activities against DLBCL in vitro and in vivo

The transcriptional repressor B cell lymphoma 6 (BCL6) plays a critical role in driving tumorigenesis of diffuse large B-cell lymphoma (DLBCL). However, the therapeutic potential of inhibiting or degrading BCL6 for DLBCL has not been thoroughly understood. Herein, we reported the discovery of a series of novel BCL6-targeting PROTACs based on our previously reported N-phenyl-4-pyrimidinamine BCL6 inhibitors. The optimal compound DZ-837 degraded BCL6 with DC50 values around 600 nM and effectively inhibited the proliferation of several DLBCL cell lines. Further study indicated that DZ-837 induced significant G1 phase arrest and exhibited sustained reactivation of BCL6 downstream genes. In the SU-DHL-4 xenograft model, DZ-837 significantly inhibited tumor growth with TGI of 71.8 % at 40 mg/kg once daily. Furthermore, the combination of DZ-837 with BTK inhibitor Ibrutinib showed synergistic effects and overcame acquired resistance against DLBCL cells. Overall, our findings demonstrate that DZ-837 is an effective BCL6 degrader for DLBCL treatment as a monotherapy or in combination with Ibrutinib.

Pharmaceutical inhibition of BCL6 ameliorates resistance to imatinib in chronic myeloid leukemia

The tyrosine kinase inhibitors (TKIs) have improved overall survival of CML (chronic myeloid leukemia) patients and allow them to experience normal life expectancy. However, relapse and drug resistance remain the main challenges in the clinical treatment of CML. The B-cell lymphoma 6 (BCL6) is essential to regulation of multiple function such as immune response and lymphomagenesis in lymph node germinal cells. Recent studies have shown that BCL6 is required for the maintenance of leukemia stem cells in CML, but the expression of Bcl-6 in response to Imatinib and the underlying mechanism are still unclear. Here, we found that BCL6 is expressed at high levels in primary CML bone marrow samples and CML TKI-resistance cell lines. CML cells with higher levels of BCL6 were generally sensitive to treatment with BCL6 inhibitors, BI-3812. Treatment of CML cells with BCL6 inhibitor and TKIs suggested enhanced anti-leukemia activity. In summary, our findings suggest BCL6 as a therapeutic target for the treatment of CML.

Venetoclax resistance in acute lymphoblastic leukemia is characterized by increased mitochondrial activity and can be overcome by co-targeting oxidative phosphorylation

Deregulated apoptosis signaling is characteristic for many cancers and contributes to leukemogenesis and treatment failure in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Apoptosis is controlled by different pro- and anti-apoptotic molecules. Inhibition of anti-apoptotic molecules like B-cell lymphoma 2 (BCL-2) has been developed as therapeutic strategy. Venetoclax (VEN), a selective BCL-2 inhibitor has shown clinical activity in different lymphoid malignancies and is currently evaluated in first clinical trials in BCP-ALL. However, insensitivity to VEN has been described constituting a major clinical concern. Here, we addressed and modeled VEN-resistance in BCP-ALL, investigated the underlying mechanisms in cell lines and patient-derived xenograft (PDX) samples and identified potential strategies to overcome VEN-insensitivity. Leukemia lines with VEN-specific resistance were generated in vitro and further characterized using RNA-seq analysis. Interestingly, gene sets annotated to the citric/tricarboxylic acid cycle and the respiratory electron transport chain were significantly enriched and upregulated, indicating increased mitochondrial metabolism in VEN-resistant ALL. Metabolic profiling showed sustained high mitochondrial metabolism in VEN-resistant lines as compared to control lines. Accordingly, primary PDX-ALL samples with intrinsic VEN-insensitivity showed higher oxygen consumption and ATP production rates, further highlighting that increased mitochondrial activity is a characteristic feature of VEN-resistant ALL. VEN-resistant PDX-ALL showed significant higher mitochondrial DNA content and differed in mitochondria morphology with significantly larger and elongated structures, further corroborating our finding of augmented mitochondrial metabolism upon VEN-resistance. Using Oligomycin, an inhibitor of the complex V/ATPase subunit, we found synergistic activity and apoptosis induction in VEN-resistant BCP-ALL cell lines and PDX samples, demonstrating that acquired and intrinsic VEN-insensitivity can be overcome by co-targeting BCL-2 and the OxPhos pathway. These findings of reprogrammed, high mitochondrial metabolism in VEN-resistance and synergistic activity upon co-targeting BCL-2 and oxidative phosphorylation strongly suggest further preclinical and potential clinical evaluation in VEN-resistant BCP-ALL.

Topical application of a BCL-2 inhibitor ameliorates imiquimod-induced psoriasiform dermatitis by eliminating senescent cells

BackgroundPsoriasis is an inflammatory skin disease with unclear pathogenesis and unmet therapeutic needs. ObjectiveTo investigate the role of senescent CD4+ T cells in psoriatic lesion formation and explore the application of senolytics in treating psoriasis. MethodsWe explored the expression levels of p16INK4a and p21, classical markers of cellular senescence, in CD4+ T cells from human psoriatic lesions and imiquimod (IMQ)-induced psoriatic lesions. We prepared a senolytic gel using B-cell lymphoma 2 (BCL-2) inhibitor ABT-737 and evaluated its therapeutic efficacy in treating psoriasis. ResultsUsing multispectrum immunohistochemistry (mIHC) staining, we detected increased expression levels of p16INK4a and p21 in CD4+ T cells from psoriatic lesions. After topical application of ABT-737 gel, significant alleviation of IMQ-induced psoriatic lesions was observed, with milder pathological alterations. Mechanistically, ABT-737 gel significantly decreased the percentage of senescent cells, expression of T cell receptor (TCR) α and β chains, and expression of Tet methylcytosine dioxygenase 2 (Tet2) in IMQ-induced psoriatic lesions, as determined by mIHC, high-throughput sequencing of the TCR repertoire, and RT-qPCR, respectively. Furthermore, the severity of psoriatic lesions in CD4creTet2f/f mice was milder than that in Tet2f/f mice in the IMQ-induced psoriasis model. ConclusionWe revealed the roles of senescent CD4+ T cells in developing psoriasis and highlighted the therapeutic potential of topical ABT-737 gel in treating psoriasis through the elimination of senescent cells, modulation of the TCR αβ repertoire, and regulation of the TET2-Th17 cell pathway.

Synergistic effects of RPT1G, a first-in-class small molecule NAMPT inhibitor, with venetoclax and olaparib in hematological malignancies.

e18512 Background: MultipleBCL-2 and PARP inhibitors are currently in clinical trials, or have been approved for use, in hematological malignancies and solid tumors. Venetoclax, an inhibitor of the apoptosis regulator B-cell lymphoma-2 (BCL-2), has activity in patients with chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). PARP inhibitors, such as Olaparib, exploit synthetic lethality in homologous recombination-deficient tumors, notably in breast and ovarian cancers. However, patients treated with BCL-2 or PARP inhibitors often face relapse and refractory disease, requiring alternative strategies to counter adaptive responses. Nicotinamide Phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the nicotinamide adenine dinucleotide (NAD+) salvage pathway, is upregulated in malignancies and plays a key role in cancer metabolism (e.g., Warburg effect). NAMPT makes nicotinamide mononucleotide which is then converted to NAD+, while PARP enzymes consume NAD+, placing NAMPT directly upstream of PARP. NAMPT overexpression is associated with Venetoclax resistance in leukemia patients, highlighting the link between NAD+, mitochondrial metabolism, and BCL-2 inhibition. Consequently, NAMPT inhibition may synergize with BCL-2 or PARP inhibitors, potentially enhancing 1st-line of treatment outcomes and re-sensitizing refractory cancer cells to BCL-2 or PARP inhibition. Methods: In this study, we investigated the combination effects of Venetoclax and Olaparib with RPT1G, a novel hyperbolic NAMPT inhibitor that simultaneously inhibits and stabilizes NAMPT in a catalytically active state. RPT1G disrupts NAMPT activity without ever turning it off completely avoiding the severe on-target toxicities seen with complete NAMPT inhibitors. Several cell lines, including OCI-AML3 and MV4;11 (AML), RS4;11 (ALL), and RL (diffuse large B-cell lymphoma) were treated with RPT1G and either Venetoclax or Olaparib to determine the degree of drug interactions. In a follow up in vivo study, we treated mice in a human xenograft model using semi-resistant MV4;11 cells with RPT1G alone or in combination with Venetoclax to measure the ability of RPT1G to enhance the effects of Venetoclax. Results: RPT1G achieves significant single-agent efficacy in leukemia and lymphoma mouse xenograft models. When RTP1G is used in combination with either Venetoclax or Olaparib significant synergy is seen across a broad range of concentrations in vitro. Consistent with in vitro synergy results, in a xenograft model of human AML, mice treated with a combination of RPT1G and Venetoclax show enhanced efficacy as compared to Venetoclax alone. Conclusions: Combination of RPT1G with either Venetoclax or Olaparib synergistically enhances killing of leukemic cells and presents as an effective strategy to improve treatment outcomes for patients with diverse malignancies.

Efficacy outcomes of treatments for double exposed chronic lymphocytic leukemia/small lymphocytic lymphoma: A systematic literature review.

e19019 Background: Bruton's tyrosine kinase inhibitors (BTKis) and the B-cell lymphoma 2 inhibitor (BCL2i) venetoclax have improved outcomes and achieved durable remission in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL) in both first-line and relapsed/refractory settings. Despite advances in treatment with these targeted agents, some CLL/SLL patients remain incurable. Notably, patients who fail to respond to both BTKis and venetoclax, termed 'double-exposed,' often exhibit poor outcomes. Data on treatment efficacy for this subgroup is limited. This study systematically reviews treatments and their efficacy outcomes in double-exposed CLL/SLL patients. Methods: A comprehensive search was conducted across MEDLINE/PubMed, Embase, and Web of Science databases from inception to November 2023, using relevant keywords and MeSH terms. The search focused on identifying studies reporting treatments and efficacy outcomes in double-exposed CLL/SLL patients, irrespective of discontinuation reasons. Key efficacy outcomes included progression-free survival (PFS), overall survival (OS), and overall response rate (ORR). Results: From 3942 retrieved articles, 12 publications covering 8 unique studies (4 clinical trials and 4 observational studies) were included. The median patient age ranged from 60-69 years in clinical trials to 56-76 years in observational studies. Two clinical trials reported PFS, with pirtobrutinib-treated patients showing a median PFS of 16.8 months (95% CI, 13.2-18.7) and lisocabtagene maraleucel-treated patients demonstrating a median PFS of 13 months (95% CI,2.8-not reached). BELLWAVE-001 was the sole study reporting a median OS of 10.1 months (95%CI, 7.4-15.9) in nemtabrutinib-treated patients. ORR varied, with 58% in nemtabrutinib-treated patients and 80% in those receiving lisocabtagene maraleucel. In the four observational studies, PFS ranged from 3 months (chemoimmunotherapy) to 12 months (BTKis), and ORR ranged from 31.8% (chemoimmunotherapy) to 85.7% (CAR T-cell therapy). Conclusions: This study underscores the scarcity of clinical data addressing efficacy outcomes in double-exposed CLL/SLL patients. Treatments like pirtobrutinib and CAR-T cell therapy show promise for this group. However, the limited treatment options and efficacy data following failure on BTKis and venetoclax highlight a significant unmet medical need. Further research is necessary to comprehensively understand efficacy outcomes in the double-exposed CLL/SLL population.

Clinical pharmacokinetics and pharmacodynamics of venetoclax, a selective B-cell lymphoma-2 inhibitor.

Venetoclax, a highly potent BCL-2 inhibitor, is indicated for treatment of some hematologic malignancies as monotherapy, and/or in combination with other agents. Venetoclax pharmacokinetics has been extensively characterized in patients and healthy participants. After oral dosing, the median time to reach maximum plasma concentration ranged from 5 to 8 h and harmonic mean half-life ranged from 14 to 18 h. Food increases venetoclax bioavailability by 3-5-fold and venetoclax should be administered with food to ensure adequate and consistent bioavailability. Venetoclax is eliminated via cytochrome P450 (CYP)3A metabolism, and a negligible amount of unchanged drug is excreted in urine. Strong CYP3A/P-glycoprotein inhibitors increased venetoclax exposures (AUC) by 1.44- to 6.90-fold while a significant decrease (71%) has been observed when dosed with strong CYP3 inducers. Venetoclax does not inhibit or induce CYP enzymes or transporters. Venetoclax pharmacokinetics is not appreciably altered by age, weight, sex, but the exposure is up to twofold higher in participants from Asian countries. Mild-to-severe renal impairment or end-stage renal disease do not alter venetoclax exposures, and venetoclax is not cleared by dialysis. Although mild-to-moderate hepatic impairment does not affect venetoclax exposures, twofold higher exposure was observed in subjects with severe hepatic impairment. Venetoclax exposure is comparable across patients with different hematologic malignancies and healthy participants. Overall, venetoclax exposure is only affected by food and CYP3A modulators and is only higher in Asian subjects and subjects with severe hepatic impairment. Venetoclax exposure-response relationships are malignancy-dependent and can be different between monotherapy and combination therapy.

In silico Analysis of 1,3,4-Oxadiazoles as Potential BCL-2 Inhibitor for Cancer Treatment

The possible efficacy of 1,3,4-oxadiazoles as B-cell lymphoma 2 (BCL-2) inhibitors for cancer treatment is investigated in this study using in silico approaches such as molecular docking, ADME and toxicity prediction. Molecular docking studies predict the binding affinities and binding modes of a series of 1,3,4-oxadiazole derivatives with the BCL-2 protein. The results revealed that the compounds with strong interactions and favourable binding modes, indicating their potential as BCL-2 inhibitors. An ADMET analysis assesses the pharmacokinetic properties and potential toxicity of the identified compounds. Parameters such as absorption, distribution, metabolism, excretion and toxicity (ADMET) were evaluated to predict the suitability of these 1,3,4-oxadiazoles as drug candidates for cancer therapy. The integration of molecular docking and ADMET analysis data led to the identification and prioritization of lead compounds with potent BCL-2 inhibitory activity and favourable pharmacokinetic profiles. This research contributes to the on-going efforts in drug discovery, emphasizing the potential of 1,3,4-oxadiazoles as a class of compounds with significant anticancer properties through BCL-2 inhibition.