navitoclax (ABT 263) / AbbVie - LARVOL DELTA

Beyond BCL2 (B cell lymphoma) and BTK (Bruton tyrosine kinase) inhibitors: novel agents and resistance mechanisms for chronic lymphocytic leukemia. (PubMed, Discov Oncol) - "CLL has demonstrated acquired resistance to BTK inhibitors and BCL2 inhibitors, necessitating the development and evaluating of treatment options beyond their use. Cancer immunotherapies such as bispecific antibodies and chimeric T cell therapies present with viable therapies for CLL. Novel agents have also been developed that enhance the cytotoxic effect of T cells. Future studies may focus on the developing treatments that overcome the acquired resistance that results when treatment with standard of care targeted therapies ibrutinib and venetoclax."

IO biomarker • Journal • Review • B Cell Lymphoma • Chronic Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2

Discovery of PZ671, a highly potent and in vivo active CRBN-recruiting Bcl-xL degrader. (PubMed, RSC Med Chem) - "Previously, we reported XZ739, a CRBN-recruiting Bcl-xL PROTAC that was 20-fold more potent than its parent inhibitor ABT-263 against Bcl-xL-dependent MOLT-4 cells while reducing toxicity to human platelets...In vivo studies revealed that PZ671 could effectively inhibit MOLT-4 xenograft growth in mice but caused only a moderate and transient reduction in platelet counts following its administration. Our findings highlight the potential of CRBN-recruiting Bcl-xL degraders as promising anticancer agents with improved efficacy and manageable platelet toxicity."

Journal • Preclinical • Hematological Disorders • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • Targeted Protein Degradation • Thrombocytopenia • BCL2L1 • CRBN

A new beta-gal targeting PET imaging for precise dynamic monitoring of premature aging and senolytic treatment response (SNMMI 2025) - "A stable PET probe, 68Ga-MGal, was obtained with >95% labeling and putative purity. The probe was specifically recognized by β-Gal both in vitro and in vivo and showed an obvious dependence property on the concentration and reaction time of β-Gal. In vivo studies showed a significantly higher uptake of CT26.CL25 tumors with high expression of β-Gal after injection of 68Ga-MGal and lower uptake of CT26.WT tumors in the control group."

Fibrosis • Immunology • Oncology

Targeting the senescent surfaceome through DPP4 antibody-functionalized nanoparticles. An application to cancer therapy. (PubMed, Biomaterials) - "In this study, the induction of senescence in human melanoma cells by palbociclib is found to lead to a senescent phenotype characterized by overexpression of the membrane protein dipeptidyl peptidase 4 (DPP4), previously identified only in ageing contexts...The nanoparticle based on mesoporous silica is loaded with the senolytic navitoclax, coated with disulfide-containing poly(ethylene glycol) to generate a redox-sensitive gatekeeper (S-S-PEG), and functionalized with an antibody against the DPP4 protein...The DPP4-targeted nanoparticle effectively reduces tumor growth and selectively removes senescent cells. Taken together, this study highlights the potential of surfaceome-targeted nanoparticles, as a clinically relevant strategy for improving senolytic therapies."

Journal • Melanoma • Oncology • Solid Tumor • DPP4

Fibrocartilage repair involves chronic cellular senescence in a rat model of bone marrow stimulation. (PubMed, Osteoarthr Cartil Open) - "Some rats were treated by intra-articular (IA) injection of senolytic drugs navitoclax or dasatinib plus quercetin. Senescent cells, including neochondrocytes, are abundant within inferior repair tissue following marrow stimulation. While their fibrogenic SASP is associated with poor healing, their removal after senescence induction does not improve repair tissue quality, possibly due to the lack of a replacement chondrogenic population."

Journal • Preclinical • Immunology • Osteoarthritis • Pain • Rheumatology • CDKN2A

Dasatinib overcomes AML cells resistant to BCL2 inhibition by degrading MCL1. (PubMed, Br J Haematol) - P=N/A | "Venetoclax (VEN) combined with azacitidine has changed the paradigm of treatment of AML...We noticed that 17 (15.7%) were navitoclax-resistant (NAV-R)...Collectively, these results suggest that DASA degrades MCL1 and effectively kills AML cells. To prove this hypothesis, we designed a phase II clinical trial named VEN-R DASA-IPC 2022 067 (EUCT 2023-505846-24-00), currently enrolling VEN-R patients."

IO biomarker • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2 • BCL2L1 • CASP3 • MCL1

Drug sensitivity patterns across FAB subtypes and molecular mutations in AML. (ASCO 2025) - "M1 samples (n=22 patients) demonstrated higher sensitivity to Navitoclax (σsDSS = 15.89), while combinations with mTOR inhibitors like Navitoclax + PF-04691502 (σsDSS = 13.97) and Navitoclax + Vistusertib (σsDSS = 13.72) showed promise...M4 subtypes (n=2 patients) were most sensitive to BAY 87-2243 (σsDSS = 15.98), with dual combinations like BAY 87-2243 + Cerdulatinib (σsDSS = 14.21) and BAY 87-2243 + Pevonedistat (σsDSS = 14.13) maintaining strong responses...In M4 eos (n=9 patients), Pimasertib demonstrated notable effectiveness (σsDSS = 14.43), with dual-agent combination such as Pimasertib + SCH772984 (σsDSS = 14.24) supporting RAS/ERK pathway inhibition. Despite rare M4/M5 subtypes (n=2 patients) showing limited Refametinib sensitivity (σsDSS = 8.75), their minimal sample size precludes definitive conclusions...Likewise, mutation analysis revealed that NPM1-mutated samples showed increased sensitivity to Venetoclax (σsDSS = 13.28) and PF-04691502 (σsDSS =..."

Acute Myelogenous Leukemia • FLT3 • NPM1

Cellular Senescence Mediates Doxorubicin Chemotherapy-Induced Aortic Stiffening: Role of Glycation Stress. (PubMed, bioRxiv) - "Aortic stiffness (aortic pulse-wave velocity [PWV]), and associated mechanisms were assessed in young adult p16-3MR mice, a model that allows for genetic-based clearance of senescent cells with ganciclovir [GCV]. Young (4-6 month) mice were injected with Doxo and subsequently treated with GCV or the senolytic ABT263...Lastly, we demonstrate the efficacy of senolytic therapy for targeting cellular senescence, the SASP and glycation stress to prevent doxorubicin-induced aortic stiffening. These results offer a novel and clinically actionable approach to preserving vascular health in cancer survivors and mitigating CVD risk."

Journal • Cardiovascular • Oncology

Addition of navitoclax to ruxolitinib for patients with myelofibrosis with progression or suboptimal response. (PubMed, Blood Neoplasia) - P2 | "NAV+RUX was tolerable and demonstrated early improvement in disease modification parameters in this difficult-to-treat population. This trial was registered at www.ClinicalTrials.gov as #NCT03222609."

Clinical • Journal • B Cell Lymphoma • Fibrosis • Hematological Disorders • Immunology • Lymphoma • Myelofibrosis • Oncology • Thrombocytopenia • BCL2

Navitoclax, Venetoclax, and Decitabine for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia Previously Treated With Venetoclax (clinicaltrials.gov) - P1 | N=17 | Active, not recruiting | Sponsor: City of Hope Medical Center | Trial completion date: May 2025 ➔ Apr 2026 | Trial primary completion date: May 2025 ➔ Apr 2026

Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Intermittent Supplementation With Fisetin Improves Physical Function and Decreases Cellular Senescence in Skeletal Muscle With Aging: A Comparison to Genetic Clearance of Senescent Cells and Synthetic Senolytic Approaches. (PubMed, Aging Cell) - "Improvements in frailty and grip strength with fisetin were comparable to those observed with genetic-based clearance of excess p16+ senescent cells and treatment with ABT-263. Taken together, our findings provide proof-of-concept support for fisetin as a senolytic strategy to improve physical function with aging."

Journal • CDKN1A • DDIT4

BH3 mimetics targeting BCL-XL have efficacy in solid tumors with RB1 loss and replication stress. (PubMed, Nat Commun) - "Therapy with a BCL-2/BCL-XL inhibitor (navitoclax) in combination with thymidylate synthase inhibitors (raltitrexed or capecitabine) causes marked and prolonged tumor regression in prostate and breast cancer xenograft models. These findings indicate that BCL-XL inhibitors may be effective as single agents in a subset of solid tumors with RB1 loss, and that pharmacological induction of replication stress may be a broadly applicable approach for sensitizing to BCL-XL inhibitors."

IO biomarker • Journal • Breast Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • BCL2 • BCL2L1 • BIRC5 • CDKN1A • RB1

Synergistic activity of S63845 and parthenolide to overcome acquired resistance to MEK1/2 inhibitor in melanoma cells: Mechanisms and therapeutic potential. (PubMed, Biomed Pharmacother) - "Parthenolide was used in combination with S63845, ABT-263 and ABT-199, BH3-mimetics targeting anti-/pro-apoptotic protein interactions. Mechanistically, parthenolide combined with S63845 reduces the protein level of MCL-1, upregulates pro-apoptotic NOXA, and prevents S63845-induced reduction of NOXA protein. Collectively, massive apoptosis induced synergistically by parthenolide combined with S63845 in trametinib-resistant melanoma cells displaying various phenotypes justifies exploring the potential of this strategy as a future treatment option for patients with melanoma resistant to therapies targeting MAPK signaling."

Journal • Preclinical • Melanoma • Oncology • Solid Tumor • CASP3 • CASP7 • MITF

Trial Treating Relapsed Acute Lymphoblastic Leukemia With Venetoclax and Navitoclax (clinicaltrials.gov) - P1/2 | N=35 | Active, not recruiting | Sponsor: St. Jude Children's Research Hospital | Trial completion date: Mar 2025 ➔ Feb 2027

Trial completion date • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology

SEQUENTIAL ALLOGENEIC STEM CELL TRANSPLANTATION FOR VENETOCLAX-EXPOSED RELAPSED OR REFRACTORY ACUTE MYELOID LEUKEMIA OR MYELODYSPLASTIC SYNDROME WITH INCREASED BLASTS-2 (EHA 2025) - "Three different 10-day preconditioning backbone regimens were used: ACTIVE (actinomycin D 12.5 mcg/kg (days 1-3), cytarabine 20 mg/m2 (days 1-10), venetoclax 600 mg (days 1-10), De-ACTIVE (decitabine 20 mg/m2 (days 1-10) added to ACTIVE) or De-CAVE (decitabine 20 mg/m2 (days 1-10), cytarabine 20 mg/m2 (days 1-10), venetoclax 600 mg (days 1-10)...Gilteritinib, revumenib, and BCR-ABL1 inhibitor exposure was reported in 16 % (4/25), 12 % (3/25), and 8 % (2/25), respectively...Cladribine (40 %, 10/25), gilteritinib (12 %, 3/25), trametinib (16 %, 4/25), navitoclax (28 %, 7/25), and ponatinib (8 %, 2/25) were added to the preconditioning... Upfront sequential alloSCT demonstrates high antileukemic efficacy in poor-risk, R/R AML, or MDS-IB2 patients with previous venetoclax exposure."

Acute Myelogenous Leukemia • Infectious Disease • Mucositis • Myelodysplastic Syndrome • Septic Shock • Transplantation • BCR • TP53

Screening for novel senolytic compounds for skin care treatments using machine learning approach. (SID 2025) - "For the ex vivo model we used Navitoclax and quercetin as reference compounds. *identity of the compounds to be disclosed at poster presentation after IP filing"

IO biomarker • Machine learning

A senescent subpopulation of fibroblasts induce inflammation in psoriasis through APOE (SID 2025) - "Mice with fibroblast-specific deletion of APOE exhibited attenuated cutaneous inflammation in imiquimod (IMQ) models, which suggested that APOE+ fibroblasts amplified inflammatory responses...Moreover, application of ABT-263 eliminated the APOE+ fibroblasts-induced inflammation, which represents a potential strategy for control of skin inflammation. Overall, our study reveals that APOE+ fibroblasts exhibit pro-inflammatory function with senescent phenotype and promote skin inflammation of psoriasis. Targeting APOE+ fibroblasts might be a promising strategy for alleviating skin inflammation."

Clinical • Atopic Dermatitis • Dermatitis • Dermatology • Dyslipidemia • Immunology • Inflammation • Metabolic Disorders • Psoriasis • Vitiligo • APOE • CXCL1

Eliminating Senescent Cells, A New Approach to Promote Repair of the Emphysematous Lung (ATS 2025) - "Senescent cells (SC) clearance was obtained by a suicide gene (p16 promoter-driven killer gene construct in p16-ATTAC mice), senolytic drugs (ABT263 and cell-permeable FOXO4-p53 interfering peptide [FOXO4-DRI]); and p16 inactivation in p16LUC/LUC mice... PE is characterized by physical destruction of parenchymal elastic fibres and markedly increased cell senescence. Our data indicate close links between elastin dysregulation, cell senescence, and PE. Targeting senescent cells is a new therapeutic strategy to induce pulmonary repair and stimulate elastogenesis in PE."

Chronic Obstructive Pulmonary Disease • Immunology • Pulmonary Disease • Pulmonary Emphysema • Respiratory Diseases • CDKN1A • ELANE

Targeting PIK3CB/YAP1 improves the sensitivity of paclitaxel by suppressing aging in head and neck squamous tumor cells. (PubMed, Cancer Cell Int) - "High PIK3CB expression in head and neck cancers is linked to poor prognosis and advanced tumor grades. PIK3CB promotes cell proliferation and reduces aging via the YAP1 pathway. The combination of navitoclax and paclitaxel reduces tumor cell proliferation and autonomous migration ability, providing a basis for further exploration of increasing chemotherapy sensitivity."

Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • PIK3CB • YAP1

ABT-263, a BCL-2 inhibitor, selectively eliminates latently HIV-1-infected cells without viral reactivation. (PubMed, PLoS One) - "Taken together, our results demonstrate that the balance of pro- and anti-apoptotic factors is crucial for the survival of latently HIV-1-infected cells. Thus, disrupting this balance using ABT-263 or combinations having ABT-263 without proviral reactivation may be useful for developing a novel strategy to eliminate latently infected cells in individuals infected with HIV-1."

Journal • Hematological Malignancies • Human Immunodeficiency Virus • Infectious Disease • Leukemia • Oncology • CD4 • XIAP

CLADRIBINE FOR RELAPSED/REFRACTORY ACUTE MYELOID LEUKEMIA - A REAL-WORLD MULTICENTER RETROSPECTIVE STUDY. (EHA 2025) - "The addition of cladribine (Clad) to low-dose cytarabine (LDAC) with venetoclax (Ven) has shown promise in R/R AML (Steinauer et al, 2024)...All patients had prior exposure to Ven, 15 (94%) had prior exposure to azacitidine and 8 (50%) had prior allogeneic hematopoietic stem cell transplantation (AHSCT). Forteen patients (87%) received Clad-LDAC-Ven triplet, 1 patient (6%) received navitoclax as well and 1 patient (6%) received Clad-Ven with decitabine... This real-world analysis shows that in heavily pre-treated and older R/R AML patients, Clad-Ven based salvage therapy offers a therapeutic option with modest outcomes, and may serve as a bridge to AHSCT, albeit with high rates of infectious complications."

Real-world • Real-world evidence • Retrospective data • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Neutropenia • Oncology • FLT3 • IDH1 • IDH2 • KRAS • MECOM • NPM1 • TP53

B-PRECURSOR ACUTE LYMPHOBLASTIC LEUKAEMIA CAUSES PARACRINE SENESCENCE IN MESENCHYMAL STROMAL CELLS TO SUBVERT THE TREATMENT RESPONSE IN ADULT ACUTE LYMPHOBLASTIC LEUKAEMIA (EHA 2025) - "Given the prominence of senescence in SD1-exposed HS27a cells, we tested the effects of two different senolytic drugs venetoclax (BCL2i) and navitoclax (BCL2i/BCLXLi) in vitro. We show that BCR::ABL1 but not ETV6::RUNX1 or KMT2A::AFF1-expressing ALL cells, can induce paracrine senescence in HS27a MSC cells. Paracrine senescence in the stromal microenvironment may be a component of treatment response in B-ALL. Senolytic drugs screens are warranted.*First two and last two authors contributed equally"

Clinical • Stroma • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • T Acute Lymphoblastic Leukemia • ABL1 • AFF1 • CAFs • CXCL10 • CXCL8 • ETV6 • HMGB2 • IL10 • IL6 • KMT2A • LMNB1 • NFKB1 • RUNX1 • SERPINE1 • SOD2

Navitoclax, a Bcl-2/xL Inhibitor, and YM155, a Survivin Inhibitor, in Combination with Carboplatin, Effectively Inhibit Ovarian Cancer Tumor Growth. (PubMed, Mol Cancer Ther) - "Initial results showed that omipalisib, verteporfin, CA3, mitoxantrone, navitoclax, venetoclax, and YM155 had significant single-drug activity in either the ALDHlo or both the ALDHlo/ALDHhi cell populations...In vivo, the combination of navitoclax/YM155/carboplatin decreased ovarian cancer metastasis, decreased the percentage of ALDHhi ovarian cancer cells in tumors, and increased survival when compared with carboplatin treatment alone in xenograft models. Our results suggest that the combination of navitoclax/YM155/carboplatin has promise as a therapy for treating ovarian cancer."

Journal • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor • BCL2 • CA3

LINKING SENESCENCE TO MITOCHONDRIAL METABOLIC ALTERATIONS IN MESENCHYMAL STROMAL CELLS FROM MYELODYSPLASTIC SYNDROME PATIENTS (EHA 2025) - "Our data demonstrated mitochondrial metabolic alterations in MDS-MSCs associated to LD accumulation and senescent phenotype. ABT263 treatment favored mitochondrial metabolic reprogramming and lipolysis eventually ameliorating hematopoietic supportive capacity of MDS stromal cells."

Clinical • Stroma • Hematological Disorders • Hematological Malignancies • Myelodysplastic Syndrome • Oncology • CD34 • DLAT

BCL-XL INHIBITION POTENTIATES INTERFERON-INDUCED APOPTOSIS IN MPN STEM CELLS (EHA 2025) - "In aggregate, these data indicate that inhibition of Bcl-xL with navitoclax is an effective strategy to potentiate the pro-apoptotic effect of pegIFNa on Jak2VF MPN LT-HSCs. Surprisingly, the acute combined administration of Navitoclax and pegIFNa also appears more effective at rapidly normalising MPN disease parameters, suggesting that this combination may also be more effective at achieving rapid haematological responses in MPN."

Hematological Disorders • Myeloproliferative Neoplasm • Oncology • BBC3 • BCL2L1 • CASP3 • CDKN2A • JAK2 • PMAIP1 • PTPRC