navitoclax (ABT 263) / AbbVie - LARVOL DELTA

ETC-501, a novel brain penetrant MNK kinase inhibitor, potentiates TMZ-induced senescence and sensitizes glioblastoma cells to senolytic therapy (AACR 2025) - "Despite aggressive multimodal therapies, including maximal surgical resection, radiation, and temozolomide (TMZ) chemotherapy, recurrence is almost inevitable...Leveraging this enhanced senescence, we increased the susceptibility of GBM cells to the senolytic agent navitoclax, enabling targeted clearance of residual senescent cells. This "one-two punch" therapeutic strategy effectively eradicated cells that could otherwise act as reservoirs for recurrence. Our findings underscore the therapeutic potential of MNK inhibition in GBM, advancing our approach to managing GBM and potentially other malignancies characterized by senescence and SASP."

Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor

CD36-mediated endocytosis of proteolysis-targeting chimeras. (PubMed, Cell) - "Here, using biotinylated chemical-probe-based target fishing and genetic knockdown/knockin approaches, we discovered that the membrane cluster of differentiation 36 (CD36) binds to and facilitates the uptake and efficacy of diverse PROTACs (e.g., SIM1-Me, MZ1, and clinical ARV-110) and large and/or polar small-molecule drugs (e.g., rapalink-1, rapamycin, navitoclax, birinapant, tubacin, and doxorubicin) via the CD36-mediated early endosome antigen 1 (EEA1)/Ras-related protein 5A (Rab5) endosomal cascade in vitro and/or in vivo. We then devised a novel chemical endocytic medicinal chemistry strategy to improve binding of PROTACs to CD36 using structural modifications via the prodrug approach, markedly enhancing PROTAC anti-tumor efficacy through spontaneously augmenting permeability and solubility."

Journal • Oncology • Targeted Protein Degradation • CD36 • RAB5A • SCARB1

Novel therapeutic strategies targeting MECOM rearranged AMLs discovered by unbiased drug screen (AACR 2025) - "Co-targeting with BETi and other identified sensitivities such as the IAP family inhibitor (LCL161) or Bcl-xL inhibitor (navitoclax or A1155463) also exhibited synergistic lethality in 3q26.2-r AML cell lines and PD AML cells. Co-treatment of mivebresib with dactolisib or LCL161 was superior than each drug alone in reducing AML burden and improving survival. These findings demonstrate promising preclinical activity of novel BETi-based combination with IAP or Bcl-xL inhibitor against AML with EVI1 overexpression."

Acute Myelogenous Leukemia • Oncology • BCL2L1 • GATA2 • MECOM • MYC • PIK3CA • TNFA • XIAP

Exploring sensitivity and resistance to proteasome inhibitors in TP53 mutated non-small cell lung carcinoma (AACR 2025) - "However, despite initial effectiveness, these Onc-p53 NSCLC cells develop resistance to PIs with the underlying mechanisms of this resistance remaining largely unknown.Methods and We have elucidated that bortezomib (BTZ)-induced ROS initiates a cascade including the activation and nuclear translocation of NRF2, followed by the induction of ATF3 and NOXA, and ultimately apoptosis. In summary, our findings show that resistance to PIs such as BTZ in NSCLC tumors expressing Onc-p53 involves adaptations that reduce proteotoxic stress and may leverage immune checkpoint pathways. However, combining PIs with BH3-mimetics effectively restores cytotoxicity, even in BTZ-resistant cells. This suggests that targeting anti-apoptotic pathways alongside traditional therapies (e.g."

IO biomarker • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ATF3 • BCL2 • BCL2L1 • PD-L1

Concurrent inhibition of the serine/threonine protein kinase AURKB and the fatty acid oxidation enzyme CPT1A demonstrates synthetic lethality in preclinical glioblastoma models (AACR 2025) - "Remarkably, the selective AURKB inhibitor barasertib was found to potently suppress the growth of established GBM cell lines, patient-derived xenograft models, and neurosphere cultures at low, nanomolar concentrations. Furthermore, the BH3-mimetic ABT263 was found to reduce the growth of GBM lines in the context of AURKB loss of function, likely due to the heightened dependence on mitochondrial metabolism. These findings uncover a previously unappreciated role for AURKB in regulating GBM metabolism and provide a strong rationale for further developing AURKB-targeted therapies, potentially in combination with metabolic inhibitors and BH3-mimetics, to improve clinical outcomes for patients with GBM."

Preclinical • Synthetic lethality • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • AURKB • CPT1A

High-throughput screening reveals novel synergistic drug combinations for metastatic castration-resistant prostate cancer (AACR 2025) - "Metastatic castration-resistant prostate cancer (mCRPC) remains a significant clinical challenge, with patients often developing resistance to androgen receptor (AR)-axis-targeted therapies such as Abiraterone and Enzalutamide...These results guided the development of a novel triple combination therapy to simultaneously target CDK9-regulated productive RNA polymerase II phosphorylation (Enitociclib), BRD4-mediated epigenetic remodeling (Pelabresib), and pro-survival BcL-xL (Navitoclax)...These findings provide a strong rationale for clinical development of multi-drug targeted combination regimens to overcome AR-V7-driven resistance and deliver durable responses with reduced toxicity for mCRPC patients with limited treatment options. Our approach also highlights the power of HTS to unbiasedly innovate synergistic therapies while uncovering critical biological mechanisms underlying cancer drug resistance."

Metastases • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • BCL2L1 • BRD4 • CASP3 • CASP7 • CDK9

Patient-derived cell line and organoid drug screening identifies synergistic PLK1 inhibitor in combination with senolytic ABT-263 for pancreatic cancer (AACR 2025) - "Our high-throughput screen of kinases inhibitors has identified PLK1 as a lethal target in PC. PLK1 inhibition induces cellular senescence, a putative escape mechanism. The combination of PLK1 inhibitor with the senolytic, ABT-263 results in greater cell death compared to either inhibitor alone."

Combination therapy • IO biomarker • Preclinical • Oncology • Pancreatic Cancer • Solid Tumor • CASP3 • CASP7 • CDK7

The role of Bcl‑2 in controlling the transition between autophagy and apoptosis (Review). (PubMed, Mol Med Rep) - "Therapeutic strategies targeting Bcl‑2 (for example inhibitors such as venetoclax, navitoclax, obatoclax and combination therapies involving autophagy modulators) were evaluated for their potential efficacy. Future research should prioritize these areas and leverage advanced single‑cell technologies to elucidate the real‑time dynamics of Bcl‑2 in cell processes. The present review highlights the key role of Bcl‑2 in cell fate determination and highlights its potential as a therapeutic target, offering insight for the development of innovative treatments for cancer, neurodegenerative disorder and age‑related diseases."

Journal • Review • CNS Disorders • Oncology • Targeted Protein Degradation • BAX • BCL2 • BECN1

Synergistic growth-inhibitory efficacy of LSD1 and BCL-XL inhibitors in JAK2+ AML/MPN cells (AACR 2025) - "We explored the synergy between the LSD1i Iadademstat (Selleckchem), and BCL-2/BCL-XL inhibitor, Navitoclax, or the platelet-sparing BCL-XL degrader, DT2216 (Dialectic Therapeutics). In summary, JAK2+-mutant post-MPN AML cell lines and isogenic Ruxolitinib-resistant lines showed sensitivity to BCL-XL inhibitors and a synergistic increased sensitivity to these compounds when combined with low dose LSD1 inhibitor, Iadademstat. Mechanisms behind the synergy are being studied and will be reported.Summary of Glo Titer Assays and Annexin 5 Flow Cytometry Data with mean Synergy ScoresGlo Titer AssayNavitoclaxDT2216LSD1iLSD1i+NavitoclaxLSD1i+DT2216Hel ParentalIC501.3±0.2µM2±0.8µMNot Reached6.5±3 nM0.25±0.08 µMHel RRIC500.5±0.3µM1.8±0.7µMNot Reached6±3nM0.3±0.15 µMSet 2 ParentalIC500.4±0.4µM2.5±1 µMNot Reached6.5±02.5nM2±1.3 µMSet 2..."

Clinical • IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myeloproliferative Neoplasm • Oncology • BAX • BCL2 • BCL2L1 • JAK2

Selective pharmacological activation of the mitochondrial protease OMA1 inhibits tumor growth and induces regression in tumors expressing low levels of FAM210B (AACR 2025) - "Combinations of BTM-3566 with the BH3 mimetic navitoclax results in synergistic cell killing activity in select solid tumor lines in vitro. BTM-3566 targets an pathway important in mitochondrial quality control leading to tumor cell growth and regression. In vivo, drug activity correlated with low expression of RNA for the mitochondrial protein FAM210B. BTM-3566 demonstrated robust activity in vivo in solid tumors of diverse origin with low FAM210B RNA expression."

B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Esophageal Cancer • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • Uterine Cancer • ATF4 • MCL1

Direct co-targeting of Bcl-xL and Mcl-1 exhibits synergistic anti-cancer effects in AR-V7-expressing mCRPC preclinical models (AACR 2025) - "Patients often develop resistance to hormonal therapies that target the AR-axis (e.g., abiraterone, enzalutamide)...Combinations targeting Bcl-xL (A-1331852 and Navitoclax) and Mcl-1 (S63845) synergistically decreased cell viability and induced apoptotic activity via cleavage of PARP, caspase 3, and caspase 7 across AR-V7 expressing CRPC cell lines (LNCaP95, VCaP-CR, 22Rv1) as early as two hours post-treatment...Our findings provide unique insight into the dependence on Bcl-2 family proteins in mCRPC. Our findings also support further preclinical development of Bcl-xL and Mcl-1 inhibitors for mCRPC."

Preclinical • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • BCL2 • BCL2L1 • CASP3 • CASP7

Advancing precision oncology: Development and utilization of breast cancer PDX models for in vivo drug discovery (AACR 2025) - "For example, HCI-015 was sensitive to docetaxel and a Notch inhibitor but refractory to navitoclax, while HCI-043 showed high sensitivity to eribulin...Similarly, HCI-043 demonstrated 100% CR with carboplatin and eribulin. For the ER+/PR+ HCI-044 model, tamoxifen treatment resulted in PD, but eribulin achieved 100% CR, highlighting subtype-specific therapeutic responses...However, by optimizing these models and integrating patient history, researchers are advancing their fidelity and expanding their applications. These models bridge the gap between preclinical research and clinical outcomes, offering new opportunities to accelerate targeted therapy development and improve patient care."

Preclinical • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor • Triple Negative Breast Cancer • BRCA1 • BRCA2 • ER • HER-2 • PGR

Targeting CDK11 in high-risk B cell acute lymphoblastic leukemia (AACR 2025) - "Additionally, the new combination with OTS964 and navitoclax showed synergism. In future studies, we will investigate how CDK11 inhibition regulates splicing factors other than SF3B1."

IO biomarker • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Breast Cancer • Hematological Malignancies • Leukemia • Multiple Myeloma • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • BCL2L1 • BCL2L2 • CDK1 • MCL1 • SF3B1 • TP53

Inhibition of bone morphogenetic protein receptor 2 increases mitochondrial bioenergetics and synergistically enhances cell death induced by BCL 2 inhibitors in lung cancer and leukemia cells (AACR 2025) - "JL189 synergistically enhanced cell death induced by the BCL-2 inhibitors ABT-263 (navitoclax) and ABT-199 (venetoclax) in both NSCLC (A549, H1299, Calu-1) and leukemia cell lines (Jurkat, Kasumi-1, THP-1). Inhibition of BMPR2 signaling increased mitochondrial biogenesis in NSCLC and leukemia cell lines, suggesting that the cancer cells are more susceptible to mitochondrial induced cell death. BMPR2 inhibition also significantly increased cancer cell death when combined with a BCL-2 inhibitor. Priming the mitochondria with a BMPR2 inhibitor may represent a novel strategy to enhance cancer therapeutics that promote mitochondrial induced apoptosis."

Hematological Malignancies • Leukemia • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BMP2 • CASP3

Navitoclax, a Bcl-2/xL inhibitor, and YM155, a survivin inhibitor, in combination with carboplatin effectively inhibit ovarian cancer tumor growth (AACR 2025) - "Initial results showed that Omipalisib, Verteporfin, CA3, Mitoxantrone, Navitoclax, Venetoclax and YM155 had significant single drug activity in either the ALDH low or both the ALDH low/high cell populations... Our results suggest that the combination of Navitoclax/YM155/carboplatin has promise as a therapy for the treatment of OvCa."

Combination therapy • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor • BCL2 • CA3

Profiling protein-protein interactions to predict sensitivity to drugs targeting BCL2 family members in lymphoma models (AACR 2025) - "Drug sensitivity parameters were integrated with protein data using Spearman Correlation and Multiple Linear Regression (MLR, Lasso). We exposed MCL (n=10, JVM2, REC1, JEKO1, UPN1, SP49, SP53, MAVER1, GRANTA519, Z138, MINO), MZL (n=6, VL51, SSK41, Karpas1718, HC1, HAIRM, ESKOL) cell lines and MZL models of secondary resistance (MZL-RES) to idelalisib (n=2), copanlisib (n=2), ibrutinib (n=2), venetoclax (n=1) and copanlisib/venetoclax (n=2), to BCL2i (venetoclax, sonrotoclax), BCL2/BCXLi (navitoclax), and MCL1i (S63845). Anti-apoptotic inhibitors show variable heterogeneous activity in MCL and MZL models, including those resistant to PI3Ki and BTKi, which could be predicted quantifying the BCL2-family members levels and interactions using the SPID. Such an approach might have a clinical potential to predict the sensitivity of patients with mature B cell lymphomas to this class of agents."

IO biomarker • Acute Myelogenous Leukemia • B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Mantle Cell Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2 • BCL2L1

Augmenting drug responses to PARP inhibitors in high grade serous cancer with inhibitors of the anti-apoptotic protein Bcl-XL (AACR 2025) - "If treating the patients with a PARPi makes cancer cells dependent on Bcl-xL then adding an inhibitor of Bcl-xL to their treatment might overcome resistance to Olaparib and cause the cancer cells to die.To test this, we have initiated companion studies for a clinical trial in which patients that have had a recurrence after receiving platinum-based therapy will first be treated with the PARPi Olaparib and then, an inhibitor of Bcl-xL, Navitoclax, will be added to their course of treatment. Our data suggest that this approach captures the inherent heterogeneity of the disease, albeit local to the sampled site. We are employing deep learning AI algorithms to enable automated analyses of 3D confocal image stacks of organoids to infer drug responses that will be compared to patient responses in ongoing clinical trials."

IO biomarker • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor • BCL2 • BCL2L1

Molecular characterization of senescence induced by PARPi in preclinical xenograft mouse models of ovarian cancer (AACR 2025) - "Methods- We generate a tumor biobank consisting of OV1946, OV4453, TOV21G and MDAMB231 preclinical xenograft models treated with combinations of the PARP inhibitor Olaparib and ABT263. We propose that characterizing the cell fate decisions within the tumor including senescence can be used to improve drug administration patterns in combo therapies and reduce resistance. For example, this should refine targets and timing to improve chemotherapies that aim to manipulate senescence."

IO biomarker • Preclinical • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor

CDK4/6 inhibitors and endocrine therapies induce senescence with drug- and cell line-specific vulnerabilities in ERα+ breast cancer (AACR 2025) - "Live-cell imaging of MCF7 and T47D cells treated with abemaciclib and endocrine therapies (endoxifen or estrogen deprivation to mimic aromatase inhibition) at clinically relevant concentrations for eight days demonstrated prolonged growth cessation and G1 cell cycle arrest even two weeks post-drug withdrawal...For example, MCF7 and UCD4 cells responded to MCL1i and RSL3, T47D to BCLXLi and RSL3, and UCD12 to BCLXLi and Navitoclax. Notably, senolytic cocktails (e.g., RSL3, GNF7, Venetoclax, Dasatinib) at reduced concentrations (0.25 μM each) effectively eliminated senescent/senescent-like ERα+ cancer cells across all cancer cell lines, achieving 100% elimination in T47D cells...This provides preliminary evidence for the potential integration of this strategy into standard breast cancer therapy with a goal to improve recurrence-free survival and increase the cure rates for ERα+ breast cancer patients. In vivo studies are underway to evaluate this strategy in preclinical..."

IO biomarker • Preclinical • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • BCL2 • CASP3 • CASP7 • CD4 • CDKN1A • CDKN2B • ER • HMGB1 • LMNB1 • TGFB1

Discovery of XZ338, a highly potent BCL-XL degrader. (PubMed, Eur J Med Chem) - "In this study, XZ338, a highly potent and selective BCL-XL degrader derived from BCL-XL specific inhibitor A-1331852, was generated. XZ338 is 70-fold more potent than ABT-263 against MOLT-4 T-ALL cells, with over 89-fold selectivity for MOLT-4 cells over human platelets."

Journal • Hematological Disorders • Neutropenia • Oncology • T Acute Lymphoblastic Leukemia • Targeted Protein Degradation • Thrombocytopenia • BCL2L1

Construction and validation of a reliable disulfidptosis-related lncRNAs signature of the subtype, prognostic, and immune landscape in bladder cancer. (PubMed, Discov Oncol) - "Based on this study, it would be advisable to identify the key DRLs with potential prognostic value in BLCA to enhance the evaluation of clinical outcomes in this context."

Journal • Tumor mutational burden • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • CD4 • CD8 • TMB

Managing Myelofibrosis: Matching Advances in Treatments With Clinical Unmet Needs. (PubMed, Hematol Oncol) - "The janus kinase inhibitor (JAKi) ruxolitinib has been the mainstay of treatment for over a decade...Other JAKi (pacritinib, momelotinib, jaktinib) address treatment-related cytopenia, expanding the therapeutic utility of this class of agents to patients with baseline anemia or thrombocytopenia. Novel candidates exploit multiple molecular pathways, and offer the potential to improve the management of MF-associated cytopenia (imetelstat, pelabresib, navitoclax, selinexor, luspatercept, sotatercept, elritercept, LCL161, bomedemstat) and recover bone marrow fibrosis (imetelstat, pelabresib, navitoclax and bomedemstat). It remains to be seen if these newer agents can induce any remission in MF and enable patients to come off therapy, but the future is beginning to look much brighter."

Journal • Review • Fibrosis • Hematological Disorders • Immunology • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Thrombocytopenia

In vitro effects of ABT-263, a BH3 mimetic, on fibrotic phenotype in endometriotic and endometrial stromal cells. (PubMed, Gynecol Obstet Invest) - "These findings suggest that fibrosis (collagen type I) and/or myofibroblasts (key source of collagen type I) may control the proliferation of endometriotic fibroblasts. Thus, the present study does not support the current concept that fibrosis is a therapeutic target for endometriosis. Until more robust evidence is obtained to support the conclusion that regression of tissue fibrosis in endometriotic lesions is indeed beneficial to patients with endometriosis, we should be very cautious in considering fibrosis a therapeutic target for endometriosis."

Journal • Preclinical • Endometriosis • Fibrosis • Gynecology • Immunology • Women's Health • BCL2

Clearance of senescent vascular smooth muscle cells retards aging-related restenosis following bioresorbable scaffolds implantation. (PubMed, Biomaterials) - "To effectively eliminate s-VSMCs and accelerate vascular repair, two types of senolytic-coated BRS were developed and tested with ABT-263 and young plasma-derived exosomes...The senolytic coatings, with their ability to clear senescent cells, promoted vascular repair. This study offers valuable insights for potential mechanisms responsible for the elevated ISR risks associated with BRS in aged aortas and the development of advanced BRS coatings."

Journal • Atherosclerosis • Cardiovascular

Trametinib and Navitoclax in Treating Patients With Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1/2 | N=96 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Mar 2025 ➔ Mar 2026

IO biomarker • Trial completion date • Oncology • Solid Tumor • BCL2L2 • KRAS • NRAS