DT2216 / Dialectic Therap - LARVOL DELTA

The Bcl-xL specific PROTAC, DT2216, increases the sensitivity to target therapy of preclinical tumor models from different origin (AACR 2026) - "Abstract is embargoed at this time."

Late-breaking abstract • Preclinical • Oncology • BCL2L1

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

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

Inhibition of NSD2 in t(4; 14) myeloma induces changes in mitochondrial priming (ASH 2025) - "Dynamic profilingof KMS11 indicated increased priming on BCL-XL and potentially BCL2 with delta priming of 14-21% withBAD and 14% with HRK peptides (targets BCL-XL), as well as increased sensitivity to AZD4320 and DT2216(BCL-XL PROTAC)...Additionally, we found these cells were less sensitive to AZD5991 and AZD4320 thanthe control cells, suggesting loss of NDS2 in KMS18 leads to decreased priming. Dynamic mitochondrial profiling post-NSD2 inhibition in t(4; 14) myeloma displayed cell linespecific patterns, perhaps owing to the heterogenous baseline priming in this high-risk subtype... Dynamic mitochondrial profiling post-NSD2 inhibition in t(4; 14) myeloma displayed cell linespecific patterns, perhaps owing to the heterogenous baseline priming in this high-risk subtype. Themolecular basis for these differences is under current investigation and could be related to thedifferences in genes influenced by NSD2 activity in these cells. RNAseq analysis of 3 myeloma cells..."

IO biomarker • Hematological Malignancies • Multiple Myeloma • Targeted Protein Degradation • ANXA5 • BCL2L1 • FGFR3 • NSD2 • TP53

Dialectic Therapeutics Announces Dosing of First Patient in Platinum-Resistant Ovarian Cancer (PROC) (Newswise) - "The advance of DT2216 to this Phase 1b/2 trial represents a critical milestone, driven by compelling data from our Phase 1a and preclinical studies."

Platinum resistant • Trial status • Ovarian Cancer

Efficacy of a Novel BCL-XL Degrader, DT2216, in Preclinical Models of Post-Myeloproliferative Neoplasm Secondary AML (ASH 2024) - "BH3 profiling revealed that JAK2V617F iPSC-HSPCs (compared to JAK2 WT iPSC-HSPCs), JAK2-mutant cell lines and post-MPN sAML primary samples (compared to BCL-2-dependent MOLM13 cells) released more cytochrome C after treatment with the BCL-XL-specific peptide HRK-Y, PROTAC DT2216, and dual BCL-XL/BCL-2 inhibitor ABT-263...Combination of DT2216 and azacytidine (AZA), ruxolitinib or venetoclax demonstrated potent efficacy and synergistic anti-leukemia cell viability in vitro exhibiting combination indexes of <1.0 (by Calcusyn software)...Taken together, our findings highlight the survival dependence of post-MPN sAML on anti-apoptotic BCL-XL. The promising efficacy of DT2216, evidenced by reduced cell viability, synergistic effects with AZA, and in vivo activity in CDX mouse model, supports its potential as a therapeutic option for post-MPN sAML."

IO biomarker • Preclinical • Acute Myelogenous Leukemia • B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Myeloproliferative Neoplasm • Non-Hodgkin’s Lymphoma • Oncology • Targeted Protein Degradation • BCL2L1 • CD34 • GLI2 • JAK2

Targeting BCL-XL with a Novel VHL-Based BCL-XL Degrader DT-2216 in Pre-Clinical JAK2-Mutant AML Post-MPN Models (ASH 2023) - "However, the clinical utility of navitoclax, a BCL-xL and BCL-2 dual inhibitor, as demonstrated in combination with JAK2 inhibitor ruxolitinib in patients with myelofibrosis (Harrison et al...In this study, we evaluated the pre-clinical efficacy of DT2216 in combination with ruxolitinib, 5-azacytidine (AZA), or MCL-1 inhibitor S63845 in JAK2-mut AML models...CONCLUSIONS These findings highlight the promising efficacy of DT2216 in JAK2-mut AML, as evidenced by reduced cell viability, on-target degradation of BCL-xL, and synergistic anti-leukemia effects when combined with AZA, ruxolitinib or MCL-1 inhibitor. These results provide valuable insights into future therapeutic strategies for the treatment of JAK2-mut AML, particularly in the context of post-MPN AML."

IO biomarker • Preclinical • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Targeted Protein Degradation • Thrombocytopenia • BCL2L1 • JAK2

Discovery of BCL-XL Heterobifunctional Degrader with Potentially Improved Therapeutic Window and Minimal Platelet Toxicity for Hematological Malignancies (ASH 2023) - "BCL-2-targeting small molecule inhibitor venetoclax won FDA approval for chronic lymphocytic leukemia and acute myeloid leukemia...We reasoned that since earlier BCL-XL degraders used strong BCL-XL inhibitor as warhead, e.g. the warhead for DT2216 is ABT263, they could readily bind to and inhibit BCL-XL in PLT causing thrombocytopenia...In vitro toxicity profiling of NXD02 including Ames test and safety panel revealed no concerns so far. In vivo safety assessment is ongoing for NXD02 as a promising candidate for clinical development in liquid and potentially select solid tumors."

IO biomarker • Acute Myelogenous Leukemia • Chronic Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • Targeted Protein Degradation • Thrombocytopenia • Von Hippel-Lindau Syndrome • BCL2 • BCL2L1 • CASP3

First in human phase 1 study of DT2216, a selective BCL-xL degrader, in patients with relapsed/refractory solid malignancies. (PubMed, J Hematol Oncol) - P1 | "Based on the rapid recovery of transient thrombocytopenia that occurred only in the first cycle and the degradation of BCL-XL in peripheral leukocytes, the RP2D of DT2216 is 0.4 mg/kg IV BIW. (NCT04886622)."

First-in-human • Journal • P1 data • Hematological Disorders • Oncology • Solid Tumor • Targeted Protein Degradation • Thrombocytopenia • BCL2L1

Uncovering Therapeutic Vulnerabilities in Adverse-Risk Pediatric Acute Myeloid Leukemia (ASH 2024) - "Navitoclax or DT2216 combined with the standard of care drug cytarabine further reduced leukemic burden in xenograft models of AMKL (Gress, 2024). In vivo validation studies to confirm anti-leukemic activity are in progress. In line with these findings, a salvage therapeutic regimen including venetoclax was used as a bridge-to-transplant strategy in a case of primary refractory PICALM : : MLLT10 AML.Overall, these results underscore the importance of assessing susceptibility to BH3 mimetics in adverse-risk pediatric AML, including those with TP53 alterations, in the context of functional precision medicine strategies."

Clinical • IO biomarker • Acute Myelogenous Leukemia • Developmental Disorders • Genetic Disorders • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Pediatrics • Targeted Protein Degradation • BCL2L1 • BCL2L2 • CBFA2T3 • CD33 • CD34 • GLIS2 • KIT • KMT2A • MLLT10 • NUP98 • PTPRC • TP53

Mitochondrial Priming Is Heterogenous in t(4; 14) Multiple Myeloma and Can be Induced By Inhibition of NSD2 (ASH 2024) - "Consistent with these findings, TKO cells were found to be more sensitive to venetoclax, the BCL2/BCLXL inhibitor AZD4320 and the BCLXL PROTAC DT2216. Conclusions : Mitochondrial priming is heterogenous in t(4; 14) MM which likely explains the lack of responses to venetoclax. However, inhibition or loss of NSD2 results in increased priming and sensitivity to BCLXL and possibly BCL2 inhibition raising the possibility of combination therapy for targeting this high-risk form of myeloma."

IO biomarker • Hematological Malignancies • Multiple Myeloma • Oncology • Targeted Protein Degradation • ANXA5 • BCL2L1 • MCL1 • NSD2 • PTPRC

Phase 1b trial of BCL-XL degrader DT2216 and weekly paclitaxel in recurrent platinum-resistant ovarian cancer (AACR-NCI-EORTC 2025) - P1 | "DT2216 is a proteolysis targeting chimera (PROTAC) degrader of BCL-XL, comprised of a VHL E3 ubiquitin ligase ligand and an ABT-263 moiety based BCL-XL binder that targets BCL-XL to VHL for ubiquitination and proteasomal degradation. Translational objectives include measuring the pharmacokinetics of DT2216 and paclitaxel when given in combination; quantitating BCL-XL levels in peripheral white blood cells to measure DT2216-mediated degradation of BCL-XL; and evaluating candidate biomarkers of response to DT2216 plus paclitaxel. Approximately 30 patients are expected to enroll."

P1 data • Platinum resistant • Epithelial Ovarian Cancer • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor • BCL2L1 • VHL

Quiescent OXPHOS-High Triple-Negative Breast Cancer Cells That Persist After Chemotherapy Depend on BCL-XL for Survival. (PubMed, Cells) - "Interestingly, inhibition of BCL-XL in doxorubicin-persistent OXPHOS-high TNBC cells rapidly abrogated mitochondrial elongation and respiratory function, followed by caspase 3/7 activation and cell death. The platelet-sparing proteolysis-targeted chimera (PROTAC) BCL-XL degrader DT2216 enhanced the efficacy of doxorubicin against TNBC xenografts in vivo without induction of thrombocytopenia that is often observed with the first-generation BCL-XL inhibitors, supporting the development of this combinatorial treatment strategy for eliminating dormant tumor cells that persist after treatment with anthracycline-based chemotherapy."

Journal • Breast Cancer • Hematological Disorders • Oncology • Solid Tumor • Targeted Protein Degradation • Thrombocytopenia • Triple Negative Breast Cancer • BCL2 • BCL2L1 • CASP3 • CASP7

BCL-xL dependency in chromophobe renal cell carcinoma. (PubMed, Cancer Gene Ther) - "We combined A-1331852 and S63845 with IKE or RSL3 (ferroptosis-inducing drugs). These data indicate that BCL-xL maintains ChRCC cell survival by suppressing apoptosis. The BCL-xL-specific PROTAC DT2216, currently in clinical trials, may provide an opportunity for ChRCC therapy."

Journal • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Targeted Protein Degradation • BCL2L1 • CASP3

Quiescent OXPHOS-high triple-negative breast cancer cells that persist after chemotherapy depend on BCL-XL for survival. (PubMed, bioRxiv) - "Interestingly, inhibition of BCL-XL in doxorubicin-persistent OXPHOS-high TNBC cells rapidly abrogated mitochondrial elongation and respiratory function, followed by caspase 3/7 activation and cell death. The platelet-sparing proteolysis targeted chimera (PROTAC) BCL-XL degrader DT2216 enhanced the efficacy of doxorubicin against TNBC xenografts in vivo without induction of thrombocytopenia that is often observed with the first-generation BCL-XL inhibitors, supporting the development of this combinatorial treatment strategy for eliminating dormant tumor cells that persist after treatment with anthracycline-based chemotherapy."

Journal • Breast Cancer • Hematological Disorders • Oncology • Solid Tumor • Targeted Protein Degradation • Thrombocytopenia • Triple Negative Breast Cancer • BCL2 • BCL2L1 • CASP3 • CASP7

De novo pyrimidine biosynthesis inhibition synergizes with BCL-XL targeting in pancreatic cancer. (PubMed, Nat Commun) - "The combination of DHODH inhibition with Brequinar and BCL-XL degradation by DT2216, a proteolysis targeting chimera (PROTAC), significantly inhibits PDAC tumor growth. These data define mechanisms of adaptation to DHODHi and support combination therapy targeting BCL-XL in PDAC."

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

Paclitaxel-induced mitotic arrest results in a convergence of apoptotic dependencies that can be safely exploited by BCL-X L degradation to overcome cancer chemoresistance. (PubMed, bioRxiv) - "In HGSOC xenografts, targeted degradation of BCL-XL using the platelet-sparing proteolysis-targeting chimera (PROTAC) DT2216 matches the efficacy of paclitaxel monotherapy while avoiding the chronic thrombocytopenia induced by BCL-XL inhibitors such as navitoclax (ABT-263). Moreover, DT2216 treatment blunts the rapid apoptotic adaptation caused by other BCL-X L inhibitors, indicating that targeted degradation of pro-survival proteins may yield more durable responses than inhibition alone. These findings uncover a mechanistic framework for safely exploiting the apoptotic dependency convergence caused by mitotic arrest and substrate detachment and support the clinical development of BCL-XL-targeting PROTACs to overcome chemoresistance in ovarian cancer and other solid tumors."

Journal • Hematological Disorders • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Pancreatic Cancer • Solid Tumor • Targeted Protein Degradation • Thrombocytopenia • BCL2L1 • MCL1

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 | Recruiting | Sponsor: Children's Oncology Group | Initiation date: Feb 2026 ➔ Jun 2025

Trial initiation date • Hepatocellular Cancer • Oncology • Solid Tumor • BCL2