WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 558958
CAS#: 2365172-42-3 (free base)
Description: DT2216 is a potent and selective Bcl-xL-specific degrader. DT2216 is highly active against Bcl-xL-dependent T cell lymphomas. DT2216 selectively killed various Bcl-xL-dependent TCL cells including MyLa cells in vitro. In vivo, DT2216 alone was highly effective against MyLa TCL xenografts in mice without causing significant thrombocytopenia or other toxicity. Furthermore, DT2216 combined with ABT199 (a selective Bcl-2 inhibitor) synergistically reduced disease burden and improved survival in a TCL PDX mouse model dependent on both Bcl-2 and Bcl-xL.
MedKoo Cat#: 558958
Name: DT-2216
CAS#: 2365172-42-3 (free base)
Chemical Formula: C77H96ClF3N10O10S4
Exact Mass: 1540.5834
Molecular Weight: 1542.36
Elemental Analysis: C, 59.96; H, 6.27; Cl, 2.30; F, 3.70; N, 9.08; O, 10.37; S, 8.31
Related CAS #: 2365172-42-3 (free base) DT2216 HCl DT2216NC DT2216-isomer
Synonym: DT-2216; DT2216; DT 2216; DT2216 HCl,
IUPAC/Chemical Name: (2S,4R)-1-((S)-2-(7-(4-((R)-3-((4-(N-(4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-((trifluoromethyl)sulfonyl)phenyl)amino)-4-(phenylthio)butyl)piperazin-1-yl)-7-oxoheptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide
InChi Key: PXVFFBGSTYQHRO-REQIQPEASA-N
InChi Code: InChI=1S/C77H96ClF3N10O10S4/c1-51(53-18-20-55(21-19-53)70-52(2)82-50-103-70)83-73(96)66-44-61(92)48-91(66)74(97)71(75(3,4)5)85-68(93)16-12-9-13-17-69(94)90-42-36-87(37-43-90)35-33-59(49-102-62-14-10-8-11-15-62)84-65-31-30-63(45-67(65)104(98,99)77(79,80)81)105(100,101)86-72(95)56-24-28-60(29-25-56)89-40-38-88(39-41-89)47-57-46-76(6,7)34-32-64(57)54-22-26-58(78)27-23-54/h8,10-11,14-15,18-31,45,50-51,59,61,66,71,84,92H,9,12-13,16-17,32-44,46-49H2,1-7H3,(H,83,96)(H,85,93)(H,86,95)/t51-,59+,61+,66-,71+/m0/s1
SMILES Code: CC1(C)CCC(C2=CC=C(Cl)C=C2)=C(C1)CN3CCN(C4=CC=C(C(NS(=O)(C5=CC(S(C(F)(F)F)(=O)=O)=C(N[C@@H](CSC6=CC=CC=C6)CCN7CCN(C(CCCCCC(N[C@@H](C(C)(C)C)C(N8[C@@H](C[C@@H](O)C8)C(N[C@H](C9=CC=C(C%10=C(N=CS%10)C)C=C9)C)=O)=O)=O)=O)CC7)C=C5)=O)=O)C=C4)CC3
Appearance: Solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO
Shelf Life: >3 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
| Biological target: | DT2216 is a potent and selective BCL-XL degrader based on PROTAC technology. |
| In vitro activity: | Four Bcl-xL-dependent TCL cell lines (i.e., MyLa, MJ, MAC2A, and L82) were tested and all of them expressed high levels of Bcl-xL and low levels of Bim (Fig. 1a) and were relatively resistant to conventional chemotherapy drugs, but were highly sensitive to DT2216 (EC50, 5–280 nM) (Fig. 1b and Table 1). In contrast, TCL lines (DL40, SMZ1, and FEPD) found to depend on Mcl-1 for survival by BH3 profiling expressed relatively higher levels of Mcl-1 and were resistant to DT2216 (EC50 > 10,000 nM) (Fig. (Fig. 1a and Table 1). Notably, the three lines resistant to DT2216 lacked expression of Bcl-xL (Fig. 1a). All 7 cell lines expressed variable levels of Bax, Bak, and Noxa and similar levels of VHL (Fig. 1a). As we previously showed, human platelets were highly sensitive to ABT263 but very resistant to DT2216 compared with Bcl-xL-dependent TCL cells because platelets express minimal levels of VHL to degrade Bcl-xL (Fig. 1b, Table 1, and Supplementary Fig. S1A, B). Reference: J Hematol Oncol. 2020 Jul 16;13(1):95. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/32677976/ |
| In vivo activity: | DT2216 was compared to ABT263 in vivo by xenografting MyLa cells s.c. into immunodeficient mice. MyLa-engrafted mice were randomized into vehicle, ABT263 (50 mpk/qd/p.o.), or DT2216 (15 mpk/q4d/i.p.) treatment groups when their tumors reached ~ 100 mm3 (Fig. 2a). The dose of ABT263 used for this experiment was selected to avoid the ABT263 treatment-induced severe thrombocytopenia we observed in our recent study. One day after the first treatment, the blood was collected from each mouse for a CBC analysis. ABT263-treated mice had ~ 73% reduction in blood platelet counts compared to vehicle-treated mice, whereas DT2216-treated mice had ~ 16% reduction (Fig. 2b). Neither treatment significantly affected other blood cell counts (Fig. (Fig.2c,2c, d). Mice were continued on treatment until they became moribund or their tumors were close to 1000 mm3 or ulcerated. Neither ABT263 nor DT2216 significantly affected body weight (Fig. 2e). ABT263 treatment slightly slowed the tumor growth and moderately extended the median survival time of the mice (from 8 to 14.5 days) compared to vehicle treatment (Fig. 2f, g). In contrast, DT2216 treatment markedly suppressed the primary tumor growth and extended the median survival time of the mice to 29.5 days (Fig. 2f, g). More importantly, the marked tumor suppression induced by DT2216 was associated with a more than 95% reduction in Bcl-xL levels, substantial decreases in Bcl-2 and Mcl-1 levels, and significant activation of caspase-3 and cleavage of PARP in the tumors collected from the mice (Fig. 2h–m). The decreases in tumor expression of Bcl-2 and Mcl-1 after DT2216 treatment were likely due to the activation of caspase-3 and induction of MyLa cell apoptosis (as shown in Fig. 1c). In contrast, ABT263 treatment had no significant effect on the tumor expression of these Bcl-2 family proteins, nor did it induce significant activation of caspase-3 and cleavage of PARP in the tumors (Fig. 2h–m). These findings demonstrate that DT2216 is more potent against MyLa TCL cells but less toxic to platelets than ABT263 in mice. Reference: J Hematol Oncol. 2020 Jul 16;13(1):95. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/32677976/ |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 20.0 | 12.97 | |
| Ethanol | 10.0 | 6.48 |
The following data is based on the product molecular weight 1542.36 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass | 1 mg | 5 mg | 10 mg |
|---|---|---|---|
| 1 mM | 1.15 mL | 5.76 mL | 11.51 mL |
| 5 mM | 0.23 mL | 1.15 mL | 2.3 mL |
| 10 mM | 0.12 mL | 0.58 mL | 1.15 mL |
| 50 mM | 0.02 mL | 0.12 mL | 0.23 mL |
| In vitro protocol: | 1. He Y, Koch R, Budamagunta V, Zhang P, Zhang X, Khan S, Thummuri D, Ortiz YT, Zhang X, Lv D, Wiegand JS, Li W, Palmer AC, Zheng G, Weinstock DM, Zhou D. DT2216-a Bcl-xL-specific degrader is highly active against Bcl-xL-dependent T cell lymphomas. J Hematol Oncol. 2020 Jul 16;13(1):95. doi: 10.1186/s13045-020-00928-9. PMID: 32677976; PMCID: PMC7364785. 2. Khan S, Zhang X, Lv D, Zhang Q, He Y, Zhang P, Liu X, Thummuri D, Yuan Y, Wiegand JS, Pei J, Zhang W, Sharma A, McCurdy CR, Kuruvilla VM, Baran N, Ferrando AA, Kim YM, Rogojina A, Houghton PJ, Huang G, Hromas R, Konopleva M, Zheng G, Zhou D. A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity. Nat Med. 2019 Dec;25(12):1938-1947. doi: 10.1038/s41591-019-0668-z. Epub 2019 Dec 2. PMID: 31792461; PMCID: PMC6898785. |
| In vivo protocol: | 1. He Y, Koch R, Budamagunta V, Zhang P, Zhang X, Khan S, Thummuri D, Ortiz YT, Zhang X, Lv D, Wiegand JS, Li W, Palmer AC, Zheng G, Weinstock DM, Zhou D. DT2216-a Bcl-xL-specific degrader is highly active against Bcl-xL-dependent T cell lymphomas. J Hematol Oncol. 2020 Jul 16;13(1):95. doi: 10.1186/s13045-020-00928-9. PMID: 32677976; PMCID: PMC7364785. 2. Khan S, Zhang X, Lv D, Zhang Q, He Y, Zhang P, Liu X, Thummuri D, Yuan Y, Wiegand JS, Pei J, Zhang W, Sharma A, McCurdy CR, Kuruvilla VM, Baran N, Ferrando AA, Kim YM, Rogojina A, Houghton PJ, Huang G, Hromas R, Konopleva M, Zheng G, Zhou D. A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity. Nat Med. 2019 Dec;25(12):1938-1947. doi: 10.1038/s41591-019-0668-z. Epub 2019 Dec 2. PMID: 31792461; PMCID: PMC6898785. |
1: Negi A, Voisin-Chiret AS. Strategies to Reduce the On-Target Platelet Toxicity of Bcl-xL Inhibitors: PROTACs, SNIPERs and Prodrug-Based Approaches. Chembiochem. 2022 Mar 9:e202100689. doi: 10.1002/cbic.202100689. Epub ahead of print. PMID: 35263486.
2: Khan S, Wiegand J, Zhang P, Hu W, Thummuri D, Budamagunta V, Hua N, Jin L, Allegra CJ, Kopetz SE, Zajac-Kaye M, Kaye FJ, Zheng G, Zhou D. BCL-XL PROTAC degrader DT2216 synergizes with sotorasib in preclinical models of KRASG12C-mutated cancers. J Hematol Oncol. 2022 Mar 9;15(1):23. doi: 10.1186/s13045-022-01241-3. PMID: 35260176; PMCID: PMC8905794.
3: Thummuri D, Khan S, Underwood PW, Zhang P, Wiegand J, Zhang X, Budamagunta V, Sobh A, Tagmount A, Loguinov A, Riner AN, Akki AS, Williamson E, Hromas R, Vulpe CD, Zheng G, Trevino JG, Zhou D. Overcoming Gemcitabine Resistance in Pancreatic Cancer Using the BCL-XL-Specific Degrader DT2216. Mol Cancer Ther. 2022 Jan;21(1):184-192. doi: 10.1158/1535-7163.MCT-21-0474. Epub 2021 Oct 19. PMID: 34667112; PMCID: PMC8742767.
4: He Y, Koch R, Budamagunta V, Zhang P, Zhang X, Khan S, Thummuri D, Ortiz YT, Zhang X, Lv D, Wiegand JS, Li W, Palmer AC, Zheng G, Weinstock DM, Zhou D. DT2216-a Bcl-xL-specific degrader is highly active against Bcl-xL-dependent T cell lymphomas. J Hematol Oncol. 2020 Jul 16;13(1):95. doi: 10.1186/s13045-020-00928-9. PMID: 32677976; PMCID: PMC7364785.
5: The PROTAC DT2216 Targets Cancer by Promoting BCL-XL Degradation. Cancer Discov. 2020 Feb;10(2):174. doi: 10.1158/2159-8290.CD-RW2019-185. Epub 2019 Dec 13. PMID: 34365411.
6: Khan S, Zhang X, Lv D, Zhang Q, He Y, Zhang P, Liu X, Thummuri D, Yuan Y, Wiegand JS, Pei J, Zhang W, Sharma A, McCurdy CR, Kuruvilla VM, Baran N, Ferrando AA, Kim YM, Rogojina A, Houghton PJ, Huang G, Hromas R, Konopleva M, Zheng G, Zhou D. A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity. Nat Med. 2019 Dec;25(12):1938-1947. doi: 10.1038/s41591-019-0668-z. Epub 2019 Dec 2. PMID: 31792461; PMCID: PMC6898785.
