DT2216, utilizing PROTAC technology, is a potent and selective degrader of BCL-XL, a member of the Bcl-2 family. It effectively degrades BCL-XL protein by engaging the Von Hippel-Lindau (VHL) E3 ubiquitin ligase. DT2216 targets various leukemia and cancer cells dependent on BCL-XL while being significantly less harmful to platelets[1].
体内研究
DT2216 (i.p.; 7.5, 15 mg/kg; weekly for 60 days) shows that the 15 mg/kg dosage is more effective in inhibiting the growth of MOLT-4 T-ALL xenografts in mice compared to the 7.5 mg/kg dosage[1].
体外研究
DT2216 (62.5, 125 nM; 72 hours) is lethal to MOLT-4 cells[1].
DT2216 (0.001-10 μM; 72 hour) is highly toxic to MOLT-4 cells, exhibiting an EC50 of 0.052 μM[1].
DT2216 (0.1, 0.3 μM; 24 hours) induces caspase-3-mediated apoptosis in MOLT-4 cells, relying on the involvement of BCL-2 homologous antagonist killer (BAK) and BCL-2-associated X protein (BAX)[1].
Evaluated the effect of sotorasib alone or in combination with DT2216 on KRASG12C-mutated tumor cell lines, showing that the combination significantly inhibited cell viability.
J Hematol Oncol. 2022 Mar 9;15(1):23
MIA PaCa-2 PC cells
1 µM
72 hours
Evaluated the effect of sotorasib alone or in combination with DT2216 on KRASG12C-mutated tumor cell lines, showing that the combination significantly inhibited cell viability.
J Hematol Oncol. 2022 Mar 9;15(1):23
H358 NSCLC cells
1 µM
72 hours
Evaluated the effect of sotorasib alone or in combination with DT2216 on KRASG12C-mutated tumor cell lines, showing that the combination significantly inhibited cell viability.
Evaluate the effect of DT2216 in combination with trametinib and afatinib on cell growth and cell death. Results showed that DT2216 combined with trametinib and afatinib significantly suppressed cell growth and induced cell death.
Neoplasia. 2025 Jan;59:101070
PDAC-lm1
0.5 µM
Evaluate the effect of DT2216 in combination with trametinib and afatinib on cell growth and cell death. Results showed that DT2216 combined with trametinib and afatinib significantly suppressed cell growth and induced cell death.
Neoplasia. 2025 Jan;59:101070
PDAC2
0.5 µM
Evaluate the effect of DT2216 in combination with trametinib and afatinib on cell growth and cell death. Results showed that DT2216 combined with trametinib and afatinib significantly suppressed cell growth and induced cell death.
Neoplasia. 2025 Jan;59:101070
PDAC1
0.5 µM
Evaluate the effect of DT2216 in combination with trametinib and afatinib on cell growth and cell death. Results showed that DT2216 combined with trametinib and afatinib significantly suppressed cell growth and induced cell death.
Neoplasia. 2025 Jan;59:101070
Patient-derived FLC tumor cells
10 μM to 10 nM
Assess the sensitivity of SN38 to patient-derived FLC tumor cells, showing significant sensitivity to FLC tumor cells
JCI Insight. 2022 Sep 8;7(17):e161820
FLC PDX cells
10 nM to 10 μM
48-72 hours
Evaluate the synergistic effect of DT2216 with SN38, showing additive or synergistic effects in FLC PDX cells
Evaluate toxicity to platelets, results showed DT2216 has low toxicity to platelets
Nat Med. 2019 Dec;25(12):1938-1947
MOLT-4 T-cell acute lymphoblastic leukemia cells
63 nM (DC50)
16 hours
Induce BCL-XL degradation, leading to apoptosis
Nat Med. 2019 Dec;25(12):1938-1947
SW837 CRC cells
1 µM
72 hours
Evaluate the effect of DT2216 combined with sotorasib on the viability of KRASG12C-mutated tumor cells, showing that the combination significantly inhibited cell viability.
J Hematol Oncol. 2022 Mar 9;15(1):23
MIA PaCa-2 PC cells
1 µM
72 hours
Evaluate the effect of DT2216 combined with sotorasib on the viability of KRASG12C-mutated tumor cells, showing that the combination significantly inhibited cell viability.
J Hematol Oncol. 2022 Mar 9;15(1):23
H358 NSCLC cells
1 µM
72 hours
Evaluate the effect of DT2216 combined with sotorasib on the viability of KRASG12C-mutated tumor cells, showing that the combination significantly inhibited cell viability.
J Hematol Oncol. 2022 Mar 9;15(1):23
MyLa cells
5-280 nM
72 hours
DT2216 selectively killed Bcl-xL-dependent TCL cells including MyLa cells
J Hematol Oncol. 2020 Jul 16;13(1):95
HT29
10, 100, 1000 nM
24 hours
Validate the ability of DT2216 to degrade BCL-XL in HT29 cells
Cell Death Dis. 2024 Mar 1;15(3):183
RKO
10, 100, 1000 nM
24 hours
Validate the ability of DT2216 to degrade BCL-XL in RKO cells
Cell Death Dis. 2024 Mar 1;15(3):183
LIM2405
10, 100, 1000 nM
24 hours
Validate the ability of DT2216 to degrade BCL-XL in LIM2405 cells
Cell Death Dis. 2024 Mar 1;15(3):183
LIM2551
10, 100, 1000 nM
24 hours
Validate the ability of DT2216 to degrade BCL-XL in LIM2551 cells
Cell Death Dis. 2024 Mar 1;15(3):183
COLO 201
10, 100, 1000 nM
24 hours
Validate the ability of DT2216 to degrade BCL-XL in COLO 201 cells
Cell Death Dis. 2024 Mar 1;15(3):183
Monocytic N5A AML cells
100 nM to 10 μM
72 hours
Evaluate the apoptotic effect of DT2216 on monocytic N5A AML cells, results showed monocytic N5A AML cells were resistant to DT2216 with IC50s > 10 μM
Blood Adv. 2024 Jan 9;8(1):112-129
NUP98r AMKL cells
100 nM to 1 μM
72 hours
Evaluate the apoptotic effect of DT2216 on NUP98r AMKL cells, results showed NUP98r AMKL cells were sensitive to DT2216 with IC50s < 200 nM
Blood Adv. 2024 Jan 9;8(1):112-129
CG2 AMKL cells
100 nM to 1 μM
72 hours
Evaluate the apoptotic effect of DT2216 on CG2 AMKL cells, results showed CG2 AMKL cells were sensitive to DT2216 with IC50s < 200 nM
Blood Adv. 2024 Jan 9;8(1):112-129
H1048
1 µM
24 h
Evaluate the synergistic killing effect of DT2216 and AZD8055 on BCL-XL/MCL-1 co-dependent SCLC cells
Cell Death Discov. 2023 Jan 2;9(1):1
H378
1 µM
24 h
Evaluate the synergistic killing effect of DT2216 and AZD8055 on BCL-XL/MCL-1 co-dependent SCLC cells
Cell Death Discov. 2023 Jan 2;9(1):1
DT2216 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
MOLT-4 T-ALL xenograft model
Intraperitoneal injection
15 mg/kg
Once weekly, continuous treatment
Evaluate the inhibitory effect of DT2216 on tumor growth and its impact on platelets, results showed DT2216 significantly inhibited tumor growth with low toxicity to platelets
Nat Med. 2019 Dec;25(12):1938-1947
Mice
H358, MIA PaCa-2, and SW837 xenograft models
DT2216 intraperitoneal injection, sotorasib oral
DT2216 15 mg/kg, sotorasib 10 mg/kg
DT2216 every four days, sotorasib five days a week, continuous treatment
Evaluate the antitumor efficacy of DT2216 combined with sotorasib, showing that the combination significantly inhibited tumor growth.
J Hematol Oncol. 2022 Mar 9;15(1):23
NOD/SCID mice
MyLa TCL xenograft model
Intraperitoneal injection
15 mg/kg
Every 4 days
DT2216 significantly suppressed the growth of MyLa TCL xenografts, extended the median survival time of mice, and did not cause significant thrombocytopenia or other toxicity
J Hematol Oncol. 2020 Jul 16;13(1):95
NSG mice
CG2 AMKL xenograft models
Intraperitoneal injection
15 mg/kg
Every 4 days for 4 to 6 weeks
Evaluate the therapeutic effect of DT2216 on CG2 AMKL xenograft models, results showed DT2216 significantly reduced leukemic burden and prolonged survival in mice
Blood Adv. 2024 Jan 9;8(1):112-129
NSG mice
PDAC-lm1 tumor xenograft model
Intraperitoneal injection
DT2216: 15 mg/kg
Twice weekly for 17 days
Evaluate the effect of DT2216 in combination with trametinib and afatinib on tumor growth. Results showed that the triplet regimen significantly reduced tumor growth rates and was well tolerated.
Neoplasia. 2025 Jan;59:101070
NSG mice
FLC PDX model
Intravenous or intraperitoneal injection
15 mg/kg
Twice a week for 3 weeks
Evaluate the efficacy and safety of DT2216 combined with irinotecan, showing significant synergistic effects and low toxicity in FLC PDX models
JCI Insight. 2022 Sep 8;7(17):e161820
Mice
H1048 xenograft tumor model
Intraperitoneal injection
15 mg/kg
Every four days
Evaluate the inhibitory effect of DT2216 and AZD8055 combination on SCLC xenograft tumor growth
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