- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, DT2216 / Dialectic Therap, navitoclax (ABT 263) / AbbVie
Journal: PROTAC-Mediated Dual Degradation of BCL-xL and BCL-2 Is a Highly Effective Therapeutic Strategy in Small-Cell Lung Cancer. (Pubmed Central) - Mar 31, 2024
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.
- |||||||||| DT2216 / Dialectic Therap
Bioorthogonal PROTAC prodrugs enabled by on-target activation | Poster Board #1609 (In-person; Poster Board #1609; Hall C (Ernest N. Morial Convention Center)) - Mar 12, 2024 - Abstract #ACSSp2024ACS_Sp_2899;
3 -dependent manner to produce PROTACs, which degrade POIs in cancer cells. The cr PROTAC strategy might be a general, abiotic approach to induce selective cancer cell death through the ubiquitin-proteasome pathway.
- |||||||||| Journal, IO biomarker: BCL-XL inhibitors enhance the apoptotic efficacy of BRAF inhibitors in BRAFV600E colorectal cancer. (Pubmed Central) - Mar 6, 2024
Combining encorafenib with DT2216 significantly increased apoptosis induction in vitro, while combining encorafenib with AZD0466 was well tolerated in mice and further reduced growth of BRAFV600E CRC xenografts compared to either agent alone. Collectively, these findings demonstrate that combined BRAF and BCL-XL inhibition significantly enhances apoptosis in pre-clinical models of BRAFV600E CRC and is a combination regimen worthy of clinical investigation to improve outcomes for these patients.
- |||||||||| DT2216 / Dialectic Therap, MRTX1133 / BMS
Rational targeting of BCL-xL and/or mTOR enhance the efficacy of KRASG12D inhibitor in pancreatic cancer (Section 23) - Mar 5, 2024 - Abstract #AACR2024AACR_6724;
Our data also suggests that novel KRAS inhibitors as monotherapy are likely to fail. 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.
- |||||||||| DT2216 / Dialectic Therap
Trial completion, Trial completion date: A Study of DT2216 in Relapsed/Refractory Malignancies (clinicaltrials.gov) - Jan 18, 2024
P1, N=20, Completed,
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. Recruiting --> Completed | Trial completion date: Mar 2024 --> Nov 2023
- |||||||||| DT2216 / Dialectic Therap
Targeting BCL-XL with a Novel VHL-Based BCL-XL Degrader DT-2216 in Pre-Clinical JAK2-Mutant AML Post-MPN Models (SDCC - Halls G-H) - Nov 3, 2023 - Abstract #ASH2023ASH_5583;
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.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, Walter and Eliza Hall Institute, DT2216 / Dialectic Therap, navitoclax (ABT 263) / AbbVie
Discovery of BCL-XL Heterobifunctional Degrader with Potentially Improved Therapeutic Window and Minimal Platelet Toxicity for Hematological Malignancies (Marriott Marquis - Marriott Grand) - Nov 3, 2023 - Abstract #ASH2023ASH_1028;
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.
- |||||||||| DT2216 / Dialectic Therap
Trial completion date, Trial primary completion date: A Study of DT2216 in Relapsed/Refractory Malignancies (clinicaltrials.gov) - Sep 7, 2023
P1, N=24, Recruiting,
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. Trial completion date: Jun 2023 --> Mar 2024 | Trial primary completion date: Apr 2023 --> Dec 2023
- |||||||||| DT2216 / Dialectic Therap
Journal: Bioorthogonal PROTAC Prodrugs Enabled by On-Target Activation. (Pubmed Central) - Jun 29, 2023
Inactive PROTAC prodrugs TCO-ARV-771 and TCO-DT2216 are rationally designed by conjugating a bioorthogonal trans-cyclooctenes (TCO) group into the ligand of the VHL E3 ubiquitin ligase...The results of studies accessing the viability of this strategy show that the PROTAC prodrugs are selectively activated in an integrin ??-dependent manner to produce PROTACs, which degrade POIs in cancer cells. The crPROTAC strategy might be a general, abiotic approach to induce selective cancer cell death through the ubiquitin-proteasome pathway.
- |||||||||| DT2216 / Dialectic Therap, A-1331852 / AbbVie, navitoclax (ABT 263) / AbbVie
Journal, IO biomarker: Anti-apoptotic protein BCL-XL as a therapeutic vulnerability in gastric cancer. (Pubmed Central) - Jun 19, 2023
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.
- |||||||||| DT2216 / Dialectic Therap, MRTX1133 / Mirati, Lumakras (sotorasib) / Amgen
Journal: Targeting KRAS in pancreatic cancer: Emerging therapeutic strategies. (Pubmed Central) - Jun 3, 2023
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.
- |||||||||| DT2216 / Dialectic Therap
Trial primary completion date: A Study of DT2216 in Relapsed/Refractory Malignancies (clinicaltrials.gov) - Feb 22, 2023
P1, N=24, Recruiting,
Finally, we discuss challenges associated with KRAS targeting and future directions, emphasizing pancreatic cancer. Trial primary completion date: Oct 2022 --> Apr 2023
- |||||||||| DT2216 / Dialectic Therap
Review, Journal: E3 ligase ligand optimization of Clinical PROTACs. (Pubmed Central) - Feb 4, 2023
Up to now, there are more than 600 known E3 ubiquitin ligases with different structures and functions, but only a few have developed corresponding E3 ubiquitin ligase ligands, and the ligands used to design PROTAC molecules are limited to a few types such as VHL (Von-Hippel-Lindau), CRBN (Cereblon), MDM2 (Mouse Doubleminute 2 homolog), IAP (Inhibitor of apoptosis proteins), etc. Most of the PROTAC molecules that have entered clinical trials were developed based on CRBN ligands, and only DT2216 was based on VHL ligand...In this review, we review the structure optimization process of E3 ubiquitin ligase ligands currently entering clinical trials on PROTAC molecules, summarize some characteristics of these ligands in terms of druggability, and provide some preliminary insights into their structural optimization. We hope that this review will help medicinal chemists to develop more druggable molecules into clinical studies and to realize the greater therapeutic potential of PROTAC technology.
- |||||||||| AZD8055 / AstraZeneca, DT2216 / Dialectic Therap
Preclinical, Journal, IO biomarker: 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 Central) - Jan 2, 2023
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.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, DT2216 / Dialectic Therap, navitoclax (ABT 263) / AbbVie
High Fatality CBFA2T3-GLIS2 Pediatric Acute Megakaryoblastic Leukemia Is Sensitive to BCL-XL Inhibition (ENMCC - 343-345) - Nov 4, 2022 - Abstract #ASH2022ASH_1339;
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.
- |||||||||| DT2216 / Dialectic Therap
Journal: Targeting BCL-XL in fibrolamellar hepatocellular carcinoma. (Pubmed Central) - Sep 11, 2022
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, IO biomarker: Strategies to reduce the On-target Platelet Toxicity of Bcl-xL Inhibitors: PROTACs, SNIPERs and Prodrug-based approaches. (Pubmed Central) - Jun 23, 2022
This paper also discussed the approaches that utilized the concept of the prodrugs, such as antibody-drug conjugates, phosphate prodrugs, dendrimer conjugate, and glycosylated conjugate. Various studies such as in vitro , in vivo , structure-activity relationship, and biophysical characterization of each inhibitor retrieved from these strategies are timely discussed in the paper.
- |||||||||| DT2216 / Dialectic Therap, Lumakras (sotorasib) / Amgen
Preclinical, Journal: BCL-X PROTAC degrader DT2216 synergizes with sotorasib in preclinical models of KRAS-mutated cancers. (Pubmed Central) - Apr 13, 2022
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.
- |||||||||| DT2216 / Dialectic Therap
Journal, IO biomarker: Overcoming Gemcitabine Resistance in Pancreatic Cancer Using the BCL-X Specific Degrader DT2216. (Pubmed Central) - Mar 31, 2022
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.
- |||||||||| DT2216 / Dialectic Therap
Degradation of Bcl-xL by DT2216 is lethal to T-cell acute lymphoblastic leukemia (E-Poster Website) - Mar 9, 2022 - Abstract #AACR2022AACR_7191;
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.
- |||||||||| DT2216 / Dialectic Therap, DNAJB1-PRKACA peptide vaccine / BMS, navitoclax (ABT 263) / AbbVie
Targeting Bcl-xL in fibrolamellar hepatocellular carcinoma (Section 15) - Mar 9, 2022 - Abstract #AACR2022AACR_6314;
P1
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.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie
Targeting Venetoclax-Resistant CLL By Bcl-XL Degradation (GWCC - Hall B5, Level 1) - Nov 5, 2021 - Abstract #ASH2021ASH_3871;
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.
- |||||||||| Targeting BCL-XL and BCL-2 By Protac 753B Effectively Eliminates AML Cells and Enhances Efficacy of Chemotherapy By Targeting Senescent Cells (GWCC - Hall B5, Level 1) - Nov 5, 2021 - Abstract #ASH2021ASH_3848;
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.
- |||||||||| DT2216 / Dialectic Therap
Enrollment open, Trial completion date, Trial initiation date: A Study of DT2216 in Relapsed/Refractory Malignancies (clinicaltrials.gov) - Oct 12, 2021
P1, N=24, Recruiting,
In vivo efficacy studies of 753B combined with chemotherapy in the cell line- and patient-derived xenografts are ongoing and will be updated. Not yet recruiting --> Recruiting | Trial completion date: Apr 2030 --> Apr 2023 | Initiation date: May 2021 --> Aug 2021
- |||||||||| azacitidine / Generic mfg., Neupogen (filgrastim) / Kyowa Hakko Kirin, Roche, Amgen, decitabine / Generic mfg.
[VIRTUAL] Harnessing Apoptosis in AML () - Jul 14, 2020 - Abstract #SOHO2020SOHO_122;
P1, P1/2,
However, clinical use of a dual BCL-2/BCL-XL inhibitor ABT-263 (navitoclax) was limited due to thrombocytopenia as platelets are partially dependent on BCL-XL for survival.4 More recently, a BCL-XL proteolysis-targeting chimera (PROTAC) was designed (DT2216), which causes BCL-XL degradation via interaction with the von Hippel-Lindau E3 ubiquitin ligase.37 DT2216 demonstrated antitumor efficacy in lymphoma and T-ALL xenograft murine models and caused less thrombocytopenia than ABT-263, suggesting it may provide a novel means of targeting BCL-XL in AML with a wider therapeutic index than ABT-263.37 In summary, exploiting the intrinsic apoptotic pathway in AML has emerged as a significant therapeutic strategy...Novel approaches are exploring combinations of venetoclax with immunotherapies (monoclonal antibodies or checkpoint inhibitors). Further progress will depend on targeting mechanisms of resistance, including TP53 mutations and alternative antiapoptotic proteins.
|
