^
Contact us  to learn more about
our Premium Content:  News alerts, weekly reports and conference planners
DRUG CLASS:

Bcl-xL degrader

Related drugs:
3ms
PROTAC-Mediated Dual Degradation of BCL-xL and BCL-2 Is a Highly Effective Therapeutic Strategy in Small-Cell Lung Cancer. (PubMed, Cells)
In our previous study, the first-in-class BCL-xL PROTAC, called DT2216, was shown to have synergistic antitumor activities when combined with venetoclax (formerly ABT199, BCL-2-selective inhibitor) in a BCL-xL/2 co-dependent SCLC cell line, NCI-H146 (hereafter referred to as H146), in vitro and in a xenograft model. At this dosage, 753b was well tolerated in mice, without observable induction of severe thrombocytopenia as seen with navitoclax, and no evidence of significant changes in mouse body weights. These results suggest that the BCL-xL/2 dual degrader could be an effective and safe therapeutic for a subset of SCLC patients, warranting clinical trials in future.
Journal
|
BCL2 (B-cell CLL/lymphoma 2) • BCL2L1 (BCL2-like 1)
|
Venclexta (venetoclax) • navitoclax (ABT 263) • DT2216
5ms
A Study of DT2216 in Relapsed/Refractory Malignancies (clinicaltrials.gov)
P1, N=20, Completed, Dialectic Therapeutics, Inc | Recruiting --> Completed | Trial completion date: Mar 2024 --> Nov 2023
Trial completion • Trial completion date
|
DT2216
8ms
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.
Preclinical • IO biomarker
|
JAK2 (Janus kinase 2) • BCL2L1 (BCL2-like 1)
|
BCL2 expression • MCL1 expression • JAK2 mutation
|
azacitidine • Jakafi (ruxolitinib) • navitoclax (ABT 263) • S63845 • DT2216
8ms
Enriched Signalling Pathways in Venetoclax-Relapsed Chronic Lymphocytic Leukemia (CLL) Cells and Targeting Using a Protac-Based Bcl-2/Bcl-Xl Degrader (ASH 2023)
Venetoclax is a specific inhibitor of Bcl-2, the key protein which protects CLL cells from intrinsic apoptosis, whereas the Bruton's Tyrosine Kinase (BTK) inhibitor ibrutinib kills CLL cells via blockade of B-cell receptor (BCR) signalling. In conclusion, WH25244 is a PROTAC-based Bcl-2/Bcl-xL degrader with the potential to overcome venetoclax-resistant CLL dependent on Bcl-xL and mutant Bcl-2. Relative to its precursor, navitoclax, it shows increased potency against CLL cells and decreased toxicity against platelets in vitro, due to its VHL-dependent activity and minimal expression of VHL in platelets.
IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • MCL1 (Myeloid cell leukemia 1) • BCL2L1 (BCL2-like 1) • MAP3K8 (Mitogen-Activated Protein Kinase Kinase Kinase 8) • ANXA5 (Annexin A5)
|
BCL2 expression • BCL2 mutation • MCL1 expression • BCL2 G101V • BCL2L1 mutation
|
Venclexta (venetoclax) • Imbruvica (ibrutinib) • navitoclax (ABT 263)
8ms
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.
PARP Biomarker • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • BCL2L1 (BCL2-like 1) • CASP3 (Caspase 3)
|
BCL2L1 overexpression
|
Venclexta (venetoclax) • navitoclax (ABT 263) • DT2216
9ms
CBFA2T3::GLIS2 Pediatric Acute Megakaryoblastic Leukemia is Sensitive to BCL-XL Inhibition by Navitoclax and DT2216. (PubMed, Blood Adv)
While CG2 cells were rather resistant to BCL2 genetic knockdown or selective pharmacological inhibition with Venetoclax, they were vulnerable to strategies that target the megakaryocytic pro-survival factor BCL-XL (BCL2L1), including in vitro and in vivo treatment with BCL2/BCL-XL/BCL-W inhibitor Navitoclax and DT2216, a selective BCL-XL PROTAC (proteolysis-targeting chimera) degrader developed to limit thrombocytopenia in patients. Navitoclax or DT2216 treatment in combination with low dose cytarabine further reduced leukemic burden in mice. This work extends the cellular and molecular diversity set of human AMKL models and uncovers BCL-XL as a therapeutic vulnerability in CG2 and NUP98r AMKL.
Journal • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • BCL2L1 (BCL2-like 1) • NUP98 (Nucleoporin 98 And 96 Precursor 2) • CD34 (CD34 molecule) • NCAM1 (Neural cell adhesion molecule 1) • BCL2L2 (BCL2 Like 2) • CBFA2T3 (CBFA2/RUNX1 Partner Transcriptional Co-Repressor 3) • GLIS2 (GLIS Family Zinc Finger 2)
|
Venclexta (venetoclax) • cytarabine • navitoclax (ABT 263) • DT2216
9ms
A Study of DT2216 in Relapsed/Refractory Malignancies (clinicaltrials.gov)
P1, N=24, Recruiting, Dialectic Therapeutics, Inc | Trial completion date: Jun 2023 --> Mar 2024 | Trial primary completion date: Apr 2023 --> Dec 2023
Trial completion date • Trial primary completion date
|
BCL2L1 (BCL2-like 1)
|
DT2216
11ms
BCLXL PROTAC degrader DT2216 targets secondary plasma cell leukemia addicted to BCLXL for survival. (PubMed, Front Oncol)
We analyzed 13 sPCL for their sensitivity to BH3 mimetics targeting either BCL2 (venetoclax) or BCLXL (A1155463) and showed that 3 sPCL were efficiently killed by venetoclax and 3 sPCL by A1155463. In conclusion, our study demonstrated that patients with sPCL addicted to BCLXL, a small but a very challenging group, could potentially receive therapeutic benefit from DT2216. Clinical trials of DT2216 in this subset of sPCL patients are warranted.
Journal • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • BCL2L1 (BCL2-like 1) • VHL (von Hippel-Lindau tumor suppressor)
|
Venclexta (venetoclax) • DT2216
12ms
Anti-apoptotic protein BCL-XL as a therapeutic vulnerability in gastric cancer. (PubMed, Animal Model Exp Med)
We identified BCL-XL as a promising therapeutic target in a subset of GC cases with high levels of BCL-XL protein expression. Functionally, we demonstrated that both selective BCL-XL inhibitors and VHL-based PROTAC BCL-XL can potently kill GC cells that are reliant on BCL-XL for survival. However, we found that BCL2L1 copy number variations (CNVs) cannot reliably predict BCL-XL expression, but the BCL-XL protein level serves as a useful biomarker for predicting the sensitivity of GC cells to BCL-XL-targeting compounds. Taken together, our study pinpointed BCL-XL as potential druggable target for specific subsets of GC.
Journal • IO biomarker
|
BCL2L1 (BCL2-like 1)
|
BCL2 expression
|
navitoclax (ABT 263) • A-1331852 • DT2216
1year
Targeting KRAS in pancreatic cancer: Emerging therapeutic strategies. (PubMed, Adv Cancer Res)
The inhibitors targeting G12D mutation (such as MRTX1133) have been recently developed, whereas those targeting other mutations are still lacking...In addition, we recently demonstrated that the combination of sotorasib with DT2216 (a BCL-X-selective degrader) synergistically inhibits G12C-mutated pancreatic cancer cell growth in vitro and in vivo...This chapter will review KRAS biochemistry, signaling pathways, different mutations, emerging KRAS-targeted therapies, and combination strategies. Finally, we discuss challenges associated with KRAS targeting and future directions, emphasizing pancreatic cancer.
Journal
|
KRAS (KRAS proto-oncogene GTPase) • BCL2L1 (BCL2-like 1)
|
KRAS mutation • KRAS G12D • KRAS G12V • KRAS G12
|
Lumakras (sotorasib) • MRTX1133 • DT2216
over1year
A Study of DT2216 in Relapsed/Refractory Malignancies (clinicaltrials.gov)
P1, N=24, Recruiting, Dialectic Therapeutics, Inc | Trial primary completion date: Oct 2022 --> Apr 2023
Trial primary completion date
|
BCL2L1 (BCL2-like 1)
|
DT2216
over1year
Co-targeting BCL-X and MCL-1 with DT2216 and AZD8055 synergistically inhibit small-cell lung cancer growth without causing on-target toxicities in mice. (PubMed, Cell Death Discov)
In vivo, the DT2216 + AZD8055 combination significantly inhibited the growth of cell line-derived and patient-derived xenografts and reduced tumor burden accompanied by increased survival in a genetically engineered mouse model of SCLC without causing appreciable thrombocytopenia or other normal tissue injuries. Thus, these preclinical findings lay a strong foundation for future clinical studies to test DT2216 + mTOR inhibitor combinations in a subset of SCLC patients whose tumors are co-driven by BCL-X and MCL-1.
Preclinical • Journal • IO biomarker
|
MCL1 (Myeloid cell leukemia 1) • BCL2L1 (BCL2-like 1)
|
MCL1 expression
|
AZD8055 • DT2216
over1year
Resistance to the BCL-XL degrader DT2216 in T-cell acute lymphoblastic leukemia is rare and correlates with decreased BCL-XL proteolysis. (PubMed, Cancer Chemother Pharmacol)
Resistance to DT2216 is rare in a wide variety of T-ALL cells but when it occurs is correlated with decreased BCL-XL degradation. Resistance to DT2216 in T-ALL is not predicted by initial BCL-XL or BIM protein levels, or BCL-2 or MCL-1 levels before or after treatment. These data imply that a phase 2 clinical trial of DT2216 in T-ALL should be widely available and not limited to a subset of patients.
Journal
|
BCL2 (B-cell CLL/lymphoma 2) • MCL1 (Myeloid cell leukemia 1) • BCL2L1 (BCL2-like 1)
|
DT2216
over1year
Dual BCL-XL/2 Protac 753B Not Only Potently Induces Apoptosis in Venetoclax-Resistant Primary AML Cells but Also Effectively Eliminates Chemotherapy-Induced Senescent AML Cells (ASH 2022)
We first evaluated the sensitivity of 24 genetically diverse leukemia cell lines (17 AML, 5 T-ALL, and 2 AML secondary to myeloproliferative neoplasms (MPN-AML) cell lines) to ABT263, DT2216 (a BCL-XL selective PROTAC) (Khan et.al Nat. In summary, the novel BCL-XL/2 PROTAC 753B potently reduced cell viability in leukemia cell lines with diverse genetic background, in primary AML cells including venetoclax-resistant AML blasts, and extended survival of mice harboring human AML PDX in vivo without hematologic toxicity. Our data indicate that co-targeting of BCL-2 and BCL-XL may eliminate senescent AML cells surviving Ara-C chemotherapy, supporting the utility of future combination studies in leukemia.
IO biomarker
|
FLT3 (Fms-related tyrosine kinase 3) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • BCL2 (B-cell CLL/lymphoma 2) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1) • MCL1 (Myeloid cell leukemia 1) • BCL2L1 (BCL2-like 1) • CXCL8 (Chemokine (C-X-C motif) ligand 8) • CDKN1A (Cyclin-dependent kinase inhibitor 1A)
|
FLT3-ITD mutation • NPM1 mutation • DNMT3A mutation
|
Venclexta (venetoclax) • cytarabine • navitoclax (ABT 263) • DT2216
over1year
Targeting Venetoclax Resistant CLL Using a Protac-Based BCL-2/BCL-XL Degrader (ASH 2022)
Treatment for chronic lymphocytic leukemia (CLL) is primarily based upon the use of small molecules targeting Bruton's tyrosine kinase (BTK; ibrutinib, acalabrutinib) or BCL-2 (venetoclax)...The efficacy of WH2544 and PZ18753b in treating naïve CLL cells fell in between that of venetoclax and navitoclax...In conclusion, our results suggest that venetoclax refractory CLL cells retain survival dependency on BCL-2 and BCL-xL proteins to evade apoptosis. This vulnerability can be therapeutically exploited using the BCL-2/BCL-xL dual targeting PROTACs PZ18753b and WH2544 in CLL.
IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • BTK (Bruton Tyrosine Kinase) • BCL2L1 (BCL2-like 1) • ANXA5 (Annexin A5)
|
BCL2 overexpression • BCL2 expression • BCL2 mutation • BCL2 G101V
|
Venclexta (venetoclax) • Imbruvica (ibrutinib) • Calquence (acalabrutinib) • navitoclax (ABT 263)
over1year
High Fatality CBFA2T3-GLIS2 Pediatric Acute Megakaryoblastic Leukemia Is Sensitive to BCL-XL Inhibition (ASH 2022)
We further investigated the molecular mechanism and showed that shRNA mediated knock-down or inhibition of BCL-XL, by either Navitoclax or the BCL-XL specific proteasomal degrader DT2216, results in significant induction of apoptosis in our models of AMKL...Furthermore, a genotype matched leukemic model of NUP98-KDM5A, which was presenting as monocytic (CD68+LYZ+) AML instead of AMKL, was resistant to either treatment with Venetoclax or Navitoclax whereas ML2, a MLL rearranged AML cell line, showed increased sensitivity to both Venetoclax and Navitoclax treatment...In conclusion, we generated a model of rare CG2 pediatric high-fatality leukemia that faithfully mimics the patient situation and allows biomass generation for large scale multi-omic approaches. Furthermore, we demonstrate a lineage- and genotype specific targetable dependency of pediatric AMKL towards inhibition of BCL-XL but not BCL2, that could be transferred to the clinic as a novel therapeutic option in high-risk infant leukemia.
Clinical • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • BCL2L1 (BCL2-like 1) • NUP98 (Nucleoporin 98 And 96 Precursor 2) • NCAM1 (Neural cell adhesion molecule 1) • BCL2L2 (BCL2 Like 2) • CD68 (CD68 Molecule) • CBFA2T3 (CBFA2/RUNX1 Partner Transcriptional Co-Repressor 3) • GATA1 (GATA Binding Protein 1) • GLIS2 (GLIS Family Zinc Finger 2) • KDM5A (Lysine Demethylase 5A) • ITGA2B (Integrin Subunit Alpha 2b)
|
MLL rearrangement • BCL2 expression • NCAM1 expression
|
Venclexta (venetoclax) • navitoclax (ABT 263) • DT2216
almost2years
Targeting BCL-XL in fibrolamellar hepatocellular carcinoma. (PubMed, JCI Insight)
To overcome this toxicity, we treated FLC models with DT2216, a proteolysis targeting chimera (PROTAC) that directs BCL-XL for degradation via the von Hippel-Lindau (VHL) E3 ligase, which is minimally expressed in platelets. The combination of irinotecan and DT2216 in vitro on cells directly acquired from patients or in vivo using several xenografts derived from patients with FLC demonstrated remarkable synergy and at clinically achievable doses not associated with significant thrombocytopenia.
Journal
|
BCL2L1 (BCL2-like 1)
|
irinotecan • DT2216
2years
BCL-X PROTAC degrader DT2216 synergizes with sotorasib in preclinical models of KRAS-mutated cancers. (PubMed, J Hematol Oncol)
Furthermore, DT2216 co-treatment significantly improved the antitumor efficacy of sotorasib in vivo. Collectively, our findings suggest that due to cytostatic activity, the efficacy of sotorasib is limited, and therefore, its combination with a pro-apoptotic agent, i.e., DT2216, shows synergistic responses and can potentially overcome resistance.
Preclinical • Journal
|
KRAS (KRAS proto-oncogene GTPase) • BCL2L1 (BCL2-like 1)
|
KRAS mutation
|
Lumakras (sotorasib) • DT2216
over2years
Degradation of Bcl-xL by DT2216 is lethal to T-cell acute lymphoblastic leukemia (AACR 2022)
Unlike other preclinical studies, like ABT263, DT2216 does not cause thrombocytopenia because VHL is poorly expressed in platelets. Our data suggests that the IC50 for all the T-ALL cell lines ranges from 2-100 nM, with the exception of SUP-T1, which exhibited an IC50 above 1 µM. Our data suggests that DT2216 could serve as a viable, safe, and potent alternative or addition to traditional clinical treatments of T-ALL.
PARP Biomarker • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • MCL1 (Myeloid cell leukemia 1) • BCL2L1 (BCL2-like 1) • PARP1 (Poly(ADP-Ribose) Polymerase 1) • CASP3 (Caspase 3)
|
MCL1 expression • PARP1 expression
|
navitoclax (ABT 263) • DT2216
over2years
A BCL-XL PROTAC degrader DT2216 synergizes with KRASG12C inhibitors for effectively treating KRASG12C-mutated cancers (AACR 2022)
Our findings suggest that due to cytostatic activity, the efficacy of sotorasib is limited, and therefore its combination with a pro-apoptotic agent DT2216 shows synergistic responses and can potentially overcome resistance.
IO biomarker
|
KRAS (KRAS proto-oncogene GTPase) • BCL2 (B-cell CLL/lymphoma 2) • BCL2L1 (BCL2-like 1)
|
KRAS mutation • BCL2 expression
|
Lumakras (sotorasib) • DT2216
over2years
Targeting Bcl-xL in fibrolamellar hepatocellular carcinoma (AACR 2022)
FLC is driven by a fusion oncokinase, DNAJB1-PRKACA, that arises from a deletion fusing exon 1 of DNAJB1 and exons 2-10 of PRKACA, the catalytic subunit of protein kinase A. Expression of this chimeric oncokinase is capable of recapitulating the key histologic and transcriptomic features of FLC...Unfortunately, Navitoclax has an on-target and dose-limiting toxicity of thrombocytopenia, which limits its clinical application...In conclusion, TOPO1 and Bcl-xL prove to be promising targets of interest in FLC. Targeting both with DT2216 and irinotecan leads to tumor shrinkage in pre-clinical models and offer a potential therapeutic/pharmacological intervention for FLC.
IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • BCL2L1 (BCL2-like 1) • DNAJB1 (DnaJ Heat Shock Protein Family (Hsp40) Member B1) • PRKCA (Protein Kinase C Alpha)
|
irinotecan • navitoclax (ABT 263) • DT2216 • DNAJB1-PRKACA peptide vaccine
over2years
Targeting Venetoclax-Resistant CLL By Bcl-XL Degradation (ASH 2021)
Our results show that exposing primary CLL samples (n=4) from treatment-naïve patients to the Bcl-xL degrader DT2216 is associated with apoptosis at concentrations known to be non-toxic to platelets (EC50 = 162 nM at 18 hr treatment). However, venetoclax-resistant CLL cells undergo a shift in dependence to alternative Bcl-2 family proteins, such as Bcl-xL and Mcl-1, as a mechanism for resistance to apoptosis. Thus, resistant CLL represents an excellent setting in which to continue testing the efficacy of these potent Bcl-xL degraders, to overcome resistance to Bcl-2 inhibitors.
IO biomarker
|
TP53 (Tumor protein P53) • MCL1 (Myeloid cell leukemia 1) • BCL2L1 (BCL2-like 1)
|
TP53 mutation • BCL2L1 overexpression • BCL2 expression • BCL2 G101V
|
Venclexta (venetoclax) • DT2216
over2years
Targeting BCL-XL and BCL-2 By Protac 753B Effectively Eliminates AML Cells and Enhances Efficacy of Chemotherapy By Targeting Senescent Cells (ASH 2021)
We first evaluated the sensitivity of genetically diverse 17 leukemia cell lines, including 10 AML, 5 T-ALL and 2 MPN-AML to BCL-XL/BCL-2 dual inhibitor ABT263, 1 st generation BCL-XL PROTAC DT2216 ( Khan et al., Nature Medicine 2019 ) and BCL-XL/BCL-2 PROTAC 753B...We found that Ara-C indeed induced cellular senescence (SnCs) in MOLM-14 and Kasumi-1 AML cells, as manifested by increased cell size, induction of senescence-associated β-galactosidase activity (Fig...753B induced 50% cell killing at concentration of 1.3 μM, and nearly complete cell killing when combined with 5nM S63845 in OCI-AML2 at 24hr (Fig.1H), suggesting a synergistic effect in inducing apoptosis...753B showed potency comparable to ABT-263 in 15 AML samples, including 9 Venetoclax-resistant samples defined as IC50>1 μM (median IC 50 , 753B - 0.197 μM; ABT-263 - 0.280 μM) (Fig...In summary, BCL-XL/BCL-2 PROTAC 753B potently reduced cell viability through induction of apoptosis, and eliminated chemotherapy-induced senescent leukemia cells. In vivo efficacy studies of 753B combined with chemotherapy in the cell line- and patient-derived xenografts are ongoing and will be updated.
Clinical • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • IL6 (Interleukin 6) • BCL2L1 (BCL2-like 1) • CD34 (CD34 molecule) • IL18 (Interleukin 18) • CDKN1A (Cyclin-dependent kinase inhibitor 1A) • IL1B (Interleukin 1, beta)
|
Venclexta (venetoclax) • cytarabine • navitoclax (ABT 263) • S63845 • DT2216
over2years
Overcoming Gemcitabine Resistance in Pancreatic Cancer Using the BCL-X Specific Degrader DT2216. (PubMed, Mol Cancer Ther)
Their synergistic antitumor activity is attributable to DT2216-induced degradation of BCL-XL and concomitant suppression of MCL-1 by GEM. Our results suggest that DT2216-mediated BCL-XL degradation augments the antitumor activity of GEM and their combination could be more effective for pancreatic cancer treatment.
Journal • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • MCL1 (Myeloid cell leukemia 1) • BCL2L1 (BCL2-like 1)
|
BCL2 overexpression
|
gemcitabine • DT2216
over2years
A Study of DT2216 in Relapsed/Refractory Malignancies (clinicaltrials.gov)
P1, N=24, Recruiting, Dialectic Therapeutics, Inc | Not yet recruiting --> Recruiting | Trial completion date: Apr 2030 --> Apr 2023 | Initiation date: May 2021 --> Aug 2021
Clinical • Enrollment open • Trial completion date • Trial initiation date
|
BCL2L1 (BCL2-like 1)
|
DT2216