DT2216 is a proteolysis targeting chimera (PROTAC), and targets Bcl-xL for degradation in T-cell lymphomas that depend on the overexpressed proteins of the Bcl-2 family, such as Bcl-2, Bcl-xL, and Mcl-1[1,2].
DT2216 inhibited G-68 cells with IC50 value of 4.02 μM (72hours). Combination of 0.1μM DT2216 and 0.1μM gemcitabine treatment synergistically kills pancreatic cancer cells in vitro [3].
DT2216 showed remarkable effects in xenograft mouse model of human T-cell lymphoma (MyLa, MJ, MAC2A, and L82 cell lines) and T-cell prolymphocytic leukemia (T-PLL), with reduced platelet toxicity compared with ABT263 [1]. DT2216 effect was also present in a patient-derived xenograft tumor model of resistant T-cell ALL, when DT2216 was combined with vincristine, dexamethasone, and L-asparaginase. The median overall survival of mice reached 72 days with combination treatment versus 55 days with DT2216 monotherapy, and 47 days with chemotherapy alone [4].
References:
[1]. He Y, Koch R, Budamagunta V, et al. DT2216—a Bcl-xL-specific degrader is highly active against Bcl-xL-dependent T cell lymphomas[J]. Journal of hematology & oncology, 2020, 13(1): 1-13.
[2]. Khan, S.; Zhang, X.; Lv, D.; Zhang, Q.; He, Y.; Zhang, P.; Liu, X.; Thummuri, D.; Yuan, Y.; Wiegand, J.S.; et al. A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity. Nat Med. 2019, 25, 1938-1947.
[3]. Thummuri D, Khan S, Underwood P W, et al. Overcoming Gemcitabine Resistance in Pancreatic Cancer Using the BCL-XL-Specific Degrader DT2216[J]. Molecular cancer therapeutics, 2022, 21(1): 184-192.
[4]. Wolska-Washer A, Smolewski P. Targeting protein degradation pathways in tumors: Focusing on their role in hematological malignancies[J]. Cancers, 2022, 14(15): 3778.
DT2216 是一种蛋白水解靶向嵌合体 (PROTAC)，靶向 Bcl-xL 降解依赖于 Bcl-2 家族过表达蛋白（例如 Bcl-2、Bcl-xL 和 Mcl）的 T 细胞淋巴瘤-1[1,2].
DT2216 抑制 G-68 细胞，IC50 值为 4.02 μM（72 小时）。 0.1μM DT2216 和 0.1μM 吉西他滨联合治疗可在体外协同杀死胰腺癌细胞[3]。
DT2216 在人 T 细胞淋巴瘤（MyLa、MJ、MAC2A 和 L82 细胞系）和 T 细胞幼淋巴细胞白血病 (T-PLL) 的异种移植小鼠模型中显示出显着效果，与 ABT263 相比血小板毒性降低 [1]。当 DT2216 与长春新碱、地塞米松和 L-天冬酰胺酶联合使用时，DT2216 效应也存在于耐药 T 细胞 ALL 患者来源的异种移植肿瘤模型中。联合治疗组小鼠的中位总生存期达到 72 天，而 DT2216 单药治疗组为 55 天，单独化疗组为 47 天[4]。