DT2216 / Dialectic Therap - LARVOL DELTA

Genome-wide CRISPR screens identify an RXR-MYLIP-LDLR axis regulating BH3 mimetic sensitivity in peripheral T-cell lymphomas. (PubMed, Oncogene) - "MYLIP deletion enhanced the cytotoxicity of navitoclax, venetoclax, and the BCL-XL-selective degrader DT2216 across multiple PTCL models. Transcriptomic analyses of primary PTCL samples revealed reduced MYLIP expression in ALK-positive anaplastic large cell lymphoma and genetically defined subsets of nodal T follicular helper cell lymphomas. These findings uncover an RXR-MYLIP-LDLR axis that links cholesterol metabolism to apoptotic susceptibility, offering mechanistic insight into BH3 mimetic sensitivity in PTCL."

Journal • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma • Targeted Protein Degradation • ALK • BCL2L1 • LDLR • RXRB

OC240475: DT2216 + Paclitaxel in Platinum-Resistant Ovarian Cancer (clinicaltrials.gov) - P1 | N=30 | Recruiting | Sponsor: Elizabeth Stover, MD, PhD | Trial completion date: Dec 2027 ➔ Dec 2028 | Trial primary completion date: Dec 2026 ➔ Jun 2027

Platinum resistant • Trial completion date • Trial primary completion date • Oncology • Ovarian Cancer • Solid Tumor • CD4

Testing the Addition of an Anti-cancer Drug, DT2216, to the Usual Chemotherapy Treatment for Relapsed or Refractory Solid Tumors and Fibrolamellar Carcinoma (clinicaltrials.gov) - P1/2 | N=81 | Suspended | Sponsor: Children's Oncology Group | Recruiting ➔ Suspended

Trial suspension • Hepatocellular Cancer • Oncology • Solid Tumor • BCL2 • DNAJB1 • PRKACA

Dual targeting of BCL-XL and MCL-1 exposes a rapid and exploitable apoptotic vulnerability in non-small cell lung cancer. (PubMed, Cell Death Differ) - "Consistent with previous reports, BH3 mimetics alone provided only limited and heterogeneous sensitization to cisplatin across NSCLC models...Accordingly, apoptosis was fully restored by next-generation BCL-XL inhibition (A-1331852) or by PROTAC-mediated BCL-XL degradation (DT2216). Importantly, platelet-sparing BCL-XL targeting strategies retained strong synergy with MCL-1 inhibition, addressing a key translational limitation of earlier BH3-mimetic approaches. Together, these data redefine apoptotic control in NSCLC as a cooperative restraint imposed by BCL-XL and MCL-1 rather than discrete, context-dependent dependencies, revealing a rapid, p53-independent mitochondrial apoptotic vulnerability with clear therapeutic implications."

IO biomarker • Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • BCL2 • BCL2L1 • TP53

Exploring the therapeutic potential of BclxL inhibitors with distinct modes of action in a living biobank of patient-derived ex vivo ovarian cancer models (OCMs) (ESMO-Gynae 2026) - "Methods We screened a panel of 20 OCMs representing diverse disease subtypes with the BclxL PROTAC DT-2216 and the BclxL-specific BH3 mimetic A-1331852. Comparable activity of the PROTAC and BH3 mimetic, together with the clinical advancement of DT-2216, supports further translational evaluation of BclxL degraders as a less toxic therapeutic strategy. Degradation efficiency alone did not predict DT-2216 response, highlighting the need to define additional determinants of PROTAC sensitivity and resistance."

Preclinical • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor • BCL2 • BCL2L1

CLIP-TAC: A Novel Proteolysis-Targeting Degrader of BCL-XL in Multiple Myeloma (EACR 2026) - "Aims: To overcome thrombocytopenia, a proteolysis-targeting-chimera (PROTAC), called DT2216, was developed that couples navitoclax (BCLXL binder) to a von Hippel–Lindau (VHL) E3 ligase-recruiting ligand to selectively degrade BCLXL in tumour cells, while sparing platelets that lack VHL...Degradation was rescued by pre-treatment with A-1331852 (BCLXL inhibitor) or MLN-4924 (NEDD8-activating enzyme inhibitor), confirming on-target, proteasome-dependent activity...Co-targeting this compensation, either directly with MCL-1 inhibitor AMG-176 or indirectly with cyclin-dependent kinase inhibitors (CYC065, THZ1, Samuraciclib), synergistically enhanced DT2216-induced cell death... MM exhibits heterogeneous dependence on BCL-2 family proteins. BH3-profiling can identify BCLXL-reliant tumours. Targeted degradation of BCLXL with DT2216, or a novel Clip-TAC, shows therapeutic potential in MM."

Hematological Malignancies • Multiple Myeloma • Plasmacytoma • Targeted Protein Degradation • Thrombocytopenia • Von Hippel-Lindau Syndrome • BCL2 • BCL2L1

Wang Z, Skwarska A, Poigaialwar G, et al. Efficacy of a novel BCL-xL degrader, DT2216, in preclinical models of JAK2-mutated post-MPN AML. Blood. 2025;146(3):341-355. (PubMed, Blood) - No abstract available

Journal • Preclinical • Acute Myelogenous Leukemia • BCL2L1 • JAK2

ErbB family members as mediators of acquired resistance to immunotherapy in high-grade serous ovarian cancer. (ASCO 2026) - "In functional assays, EGFR inhibition with gefitinib significantly enhanced CAR-T cell-mediated killing in OVCAR3, OVCAR3IE and OVCAR3R cells...Finally, blocking anti-apoptotic signaling with Bcl-family inhibitor navitoclax, or the Bcl-xL inhibitor DT2216 restored susceptibility to both CAR-T cell and BiTEs-mediated killing. Adaptive resistance to T-cell mediated cytotoxicity appears to be mediated, at least in part, by upregulation of ErbB family members and consequent downstream Ras signaling and resistance to apoptosis. While further functional in vitro and therapeutic in vivo studies are warranted to investigate the translational potential of our findings, EGFR signaling may represent a promising target for clinical combination strategies."

IO biomarker • Preclinical • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Peritoneal Cancer • Solid Tumor • BCL2L1 • HER-2 • MUC16

Pretargeted PROTAC Strategy Enables Precise Tumor Target Degradation via Self-Assembling Peptides. (PubMed, ACS Appl Mater Interfaces) - "Using the PROTAC DT2216 as a model, this pretargeted system integrates the self-assembling peptide TPE-GK-N3 (targeting tumor integrin αvβ3 via RGD and forming surface-adherent nanofibers) and the DT2216-loaded liposome DSPE-PEG2000-DBCO...In vivo, the system demonstrated profound tumor growth suppression (about 65% inhibition) with no obvious toxicity to normal tissues. This study demonstrates a pretargeted peptide strategy for PROTAC delivery, significantly enhancing anticancer efficacy while mitigating systemic toxicity, offering a promising strategy for future PROTAC development."

Journal • Oncology • Targeted Protein Degradation • BCL2L1

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

The Bcl-xL specific PROTAC, DT2216, increases the sensitivity to target therapy of preclinical tumor models from different origin (AACR 2026) - "Moreover, when used in combinational regimen, we proved that DT2216 potentiated the efficacy of: a BRAF inhibitor (Dabrafenib) and a MEK inhibitor (Trametinib) in BRAFV600E/K melanoma cell lines; Trametinib in BRAF wild type melanoma cell lines; Dabrafenib in BRAFV600E/K colorectal cancer cell lines; a KRAS inhibitor (MRTX1133) in KRASG12D pancreatic cancer cell lines; a PARP-1 inhibitor (Olaparib) in breast and ovarian cancer cell lines...In melanoma models, DT2216 also induced a potentiating effect on ABT-199, a Bcl-2 specific inhibitor, and S63845, a Mcl-1 specific inhibitor. Finally, we validated our in vitro results by using xenograft mouse melanoma model in which DT2216 potentiated the effect of target therapy, showing a significant reduction of tumor growth and conferring a longer disease control. In conclusion, our results highlighted the relevance of targeting the Bcl-xL protein as a potential therapeutic strategy in combinatorial regimens with target therapies..."

Late-breaking abstract • Preclinical • Colorectal Cancer • Melanoma • Oncology • Ovarian Cancer • Pancreatic Cancer • Solid Tumor • BCL2 • BCL2L1 • KRAS

Targeting apoptosis to overcome cancer chemoresistance in solid tumors (AACR 2026) - "To circumvent this, we screened for agents that can indirectly modulate expression of these proteins and found that paclitaxel treatment selectively depletes MCL-1 and upregulates BCL-XL, creating a state of apoptotic convergence in which BCL-XL is forced to sequester crucial pro-apoptotic proteins (BIM, BAX, BAK) during mitotic arrest. Notably, DT2216 also reduces the RAA that is evident with conventional BCL-XL inhibitors, indicating that targeted degradation of pro-survival proteins will produce more durable therapeutic responses than inhibition alone. Collectively, these findings provide a mechanistic and translational framework for safely and effectively co-targeting MCL-1 and BCL-XL in solid tumors and support the clinical development of BCL-XL-targeting PROTACs as a promising strategy to overcome chemoresistance in ovarian cancer and other solid tumors."

IO biomarker • Oncology • Ovarian Cancer • Solid Tumor • BCL2 • BCL2L1

First in human phase 1 study of DT2216, a selective BCL-xL degrader, in patients with relapsed/refractory solid malignancies (NCT04886622) (AACR 2025) - P1 | "Small molecule inhibition of BCL-xL with navitoclax resulted in on-target, dose-limiting thrombocytopenia. Based on the rapid recovery of the transient thrombocytopenia that occurred only in the first cycle and the degradation of BCL-xL in peripheral leukocytes, the recommended phase 2 dose of DT2216 is 0.4 mg/kg IV BIW. Phase 2 clinical trials are being initiated for DT2216 in CTCL as monotherapy and in combination with chemotherapy in ovarian cancer and fibrolamellar HCC."

Clinical • First-in-human • P1 data • B Cell Lymphoma • Colorectal Cancer • Cutaneous T-cell Lymphoma • Hematological Malignancies • Hepatocellular Cancer • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Ovarian Cancer • Pancreatic Cancer • Solid Tumor • BCL2L1

The Combination of a BCL-xL PROTAC and an mTOR Inhibitor Sensitizes Pancreatic Ductal Adenocarcinoma to KRASG12D Inhibitor Treatment. (PubMed, Cancers (Basel)) - "Collectively, our findings suggest that the combination of DT2216/everolimus potentiates the anti-tumor efficacy of MRTX1133 associated with enhanced apoptosis induction and inhibition of compensatory survival signaling."

IO biomarker • Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Targeted Protein Degradation • BCL2 • BCL2L1 • KRAS • PMAIP1

A triplet therapeutic strategy targeting MEK, BCL-XL, and EGFR, for KRAS-mutant pancreatic ductal adenocarcinoma (AACR 2024) - "Trametinib (MEK inhibitor), Afatinib (pan-EGFR/HER inhibitor), and Navitoclax (BCL-XL inhibitor); or DT2216 (a BCL-XL/BCL-1 proteolysis targeting chimera, PROTAC) were explored using various combinatorial strategies. Clinical trials that assess the efficacy and safety of this strategy for patients with KRAS-mutant pancreatic cancer are warranted. Our data also suggests that novel KRAS inhibitors as monotherapy are likely to fail."

Colorectal Cancer • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • BCL2L1 • CCND1 • EGFR • KRAS

Organoid models of ovarian clear cell carcinoma for evaluating therapeutic sensitivity (AACR 2025) - "The OCCC PDO was treated with standard-of-care chemotherapies carboplatin and paclitaxel; BCL-XL inhibitor A1331852 (Selleckchem); a novel BCL-XL PROTAC degrader DT2216 (Dialectic Therapeutics); or combinations of the BCL-XL inhibitor/degrader with paclitaxel. These data suggest that BCL-XL inhibition/degradation combined with paclitaxel may be a promising treatment strategy for OCCC. Our study also demonstrates the successful establishment of OCCC PDOs and application of a microfluidic device for evaluating novel therapeutic strategies in ovarian cancer."

Clear Cell Carcinoma • Oncology • Ovarian Cancer • Solid Tumor • ARID1A • BCL2L1 • CASP3 • CASP7 • CDKN2A • CDKN2B • HER-2 • PIK3CA

Rational targeting of BCL-xL and/or mTOR enhance the efficacy of KRASG12D inhibitor in pancreatic cancer (AACR 2024) - "Our findings suggest that the single agent efficacy of MRTX1133 is limited due to apoptosis inhibition and complimentary senescence induction, and therefore its combination with DT2216 and/or everolimus is synergistic, which can potentially overcome resistance, by enhanced apoptosis and clearance of senescent cells."

Clinical • IO biomarker • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor • BCL2 • BCL2L1 • KRAS • PMAIP1

The HSP90-dependent bioorthogonal PROTAC prodrug system enables tumor-selective and enhanced protein degradation. (PubMed, J Control Release) - "The HBPROTAC system consists of two components: (1) Tz-PU, a tetrazine-conjugated HSP90 inhibitor designed for tumor-selective accumulation, and (2) TCO-caged PROTAC prodrugs (TCO-MZ1 or TCO-DT2216), which release active PROTACs (MZ1 or DT2216) through inverse electron demand Diels-Alder (IEDDA) reactions with Tz-PU...Moreover, inhibition by Tz-PU synergistically enhanced the degradation efficiency of the target proteins through HSP90-mediated signaling. The tumor-specific and enhanced degradation character of HBPROTAC was confirmed in various tumor cell lines and the melanoma mouse model, demonstrating that this strategy establishes a broadly applicable platform for tumor-specific spatiotemporal control of targeted protein degradation and diminished off-tissue on-target toxicity."

Journal • Melanoma • Oncology • Solid Tumor • Targeted Protein Degradation • BCL2L1 • BRD4 • CDC37 • HSP90AA1

Targeting BCL-XL for degradation synergizes with gemcitabine against cholangiocarcinoma. (PubMed, BMC Med) - "These findings establish XZ739 as a promising therapeutic candidate for BCL-XL-dependent CCA, highlighting its translational potential for rational combination with chemotherapy to overcome resistance while mitigating hematologic toxicity."

IO biomarker • Journal • Biliary Cancer • Cholangiocarcinoma • Hematological Disorders • Oncology • Solid Tumor • Targeted Protein Degradation • Thrombocytopenia • Von Hippel-Lindau Syndrome • BCL2 • BCL2L1 • CRBN • MCL1 • VHL

Dual inhibition of KIF11 and BCL-XL or MCL-1 rewires mitotic cell fates and efficiently kills lung cancer cells (LCC 2026) - "To evaluate its therapeutic potential, we treated a panel of NSCLC cell lines with the specific KIF11 inhibitor Filanesib (KIF11i)...Indeed, combination of KIF11i with BCL-XL-targeting PROTAC DT2216 or MCL-1-specific BH3 mimetics induced efficient cell death...However, treatment with KIF11i may promote the formation of hyperploid aggressive subclones contributing to disease progression and treatment resistance. Co-targeting of KIF11 and BCL-XL or MCL-1 might represent an efficient strategy to kill NSCLC cells and prevent the emergence of hyperploid cells, thus representing a promising new treatment approach for NSCLC."

IO biomarker • Lung Cancer • Mantle Cell Lymphoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • BCL2 • BCL2L1 • KIF11 • MCL1 • TP53

The combination of BCL-xL PROTAC and mTOR inhibitor sensitizes pancreatic ductal adenocarcinoma to KRAS G12D inhibitor treatment by enhancing apoptosis induction. (PubMed, bioRxiv) - "KRAS inhibitors, including KRAS G12D inhibitor MRTX1133, are promising therapeutics against KRAS-mutated pancreatic ductal adenocarcinoma (PDAC), but drug resistance limits their efficacy. Our study reveals that robust induction of apoptosis using a combination of BCL-xL PROTAC degrader and an mTOR inhibitor, significantly enhances MRTX1133 efficacy in PDAC models without increasing toxicity to normal tissues."

Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Targeted Protein Degradation • BCL2L1 • KRAS • PMAIP1

PROTAC-mediated degradation of Bcl-xL potentiates target therapy in preclinical melanoma models. (PubMed, J Exp Clin Cancer Res) - "Our findings provide new insights for combination therapy including Bcl-xL degradation for melanoma treatment."

Journal • Preclinical • Melanoma • Oncology • Solid Tumor • Targeted Protein Degradation • BCL2L1 • BRAF • CASP7

Fusion-specific regulation of polyamine synthesis sensitizes to BCL-XL inhibition in TCF3::PBX1+ B-ALL (ASH 2025) - "In vivo combination of DFMO + polyamine-transport inhibitor AMXT-1501 and BCL-XL PROTAC DT2216 in TCF3::PBX1+ PDX models demonstrated promising antileukemic efficacy seen byreduced leukemic burden in spleen and bone marrow at the end of treatment.Collectively, our findings identify the fusion TF TCF3::PBX1 as a previously unrecognized positive regulatorof polyamine synthesis, acting via ODC1 upregulation, positioning ODC1 as a promising target in thissubtype. We further demonstrated that targeting polyamine synthesis induces transcriptional changes inessential B-cell developmental and metabolic programs, uncovering opportunities to target syntheticlethal principles through BCL-XL. The recent approval of DFMO for neuroblastoma maintenance therapyhighlights its translational potential not only in TCF3::PBX1+ B-ALL but warrants exploration of thisrational combination in other MYC-driven and/or polyamine-addicted B-ALL, especially in therelapsed/refractory context."

Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Leukemia • Neuroblastoma • Solid Tumor • Targeted Protein Degradation • BCL2L1 • MYC • ODC1 • PBX1 • TCF3

Efficacy of a novel BCL-xL degrader, DT2216, in the treatment of triple-negative breast cancer (SABCS 2025) - "DT2216 significantly potentiated the cytotoxic effects of two commonly used chemotherapeutic agents (paclitaxel and carboplatin) across a range of concentrations, producing a robust synergistic inhibition of TNBC cell proliferation. In vivo experiments validating these in vitro data are ongoing. Together, these data indicate that the selective degradation of BCL-xL by DT2216, either as monotherapy or in combination with standard-of-care chemotherapy, could offer a novel therapeutic strategy to improve outcomes for patients with TNBC."

Clinical • IO biomarker • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BCL2 • BCL2L1 • ER

HDAC inhibitors potentiate the efficacy of antineoplastic agents in acute megakaryoblastic leukemia via dual activation of apoptosis and pyroptosis (ASH 2025) - "In vivo efficacywas tested using MEG-01-Luc-GFP CDX models in NSG mice treated with vehicle (Group A), Chidamide(Group B), DT2216 (Group C), or combination (Group D). Combining HDACinhibitors with BCL-XL-targeting agents or CAR T cells shows strong preclinical efficacy. This multimodalstrategy offers a promising avenue for treating high-risk AMKL."

Clinical • IO biomarker • Bone Marrow Transplantation • Developmental Disorders • Genetic Disorders • Hematological Malignancies • Leukemia • BCL2L1 • CASP3 • CASP8 • CASP9 • CD276 • GSDME • HMGB1 • XIAP