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DT2216 is an experimental drug from Dialectic Therapeutics that makes cancer cells destroy BCL-XL, a protein they use to avoid dying. It was designed to avoid the sharp fall in platelets that stopped earlier drugs against the same protein.
BCL-XL is a validated cancer target, but the inhibitor navitoclax (ABT-263) causes on-target, dose-limiting thrombocytopenia because platelets need BCL-XL to survive. Khan and colleagues (Nature Medicine 2019) converted it into DT2216, a PROTAC that sends BCL-XL to the VHL E3 ligase for degradation; it was more potent than navitoclax against BCL-XL-dependent leukaemia and cancer cells, considerably less toxic to platelets, and inhibited several xenograft tumours alone or with chemotherapy.
The first-in-human phase 1 study (NCT04886622; Mahadevan and colleagues, Journal of Hematology and Oncology 2025) enrolled 20 patients with relapsed or refractory solid tumours at 0.04 to 0.4 mg/kg intravenously twice weekly. There was one dose-limiting toxicity, a grade 4 thrombocytopenia that resolved within 48 hours; platelet counts recovered above 50,000 within four days in every case, stable disease was seen in 20 per cent, and 0.4 mg/kg was chosen as the recommended phase 2 dose. Dialectic lists phase 1/2 trials in fibrolamellar carcinoma (NCT06620302, with chemotherapy) and platinum-resistant ovarian cancer (NCT06964009, with paclitaxel).
A proteolysis-targeting chimera built from the BCL-XL/BCL-2 inhibitor navitoclax (ABT-263) and a ligand for the VHL E3 ligase, so BCL-XL is tagged for proteasomal degradation; VHL is poorly expressed in platelets, which are spared the on-target thrombocytopenia that limits navitoclax.
1.One end of DT2216 binds BCL-XL, a protein that keeps cancer cells alive
Background: ADC sequencing, Antigen escape (antigen loss, lineage switch), BCG-unresponsive, Castration-resistant prostate cancer (CRPC), Circulating tumour DNA (ctDNA). Also on OnCo: Resistance: how tumours escape each drug class · Lines of therapy.
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Query for this drug: (TITLE:"DT2216" OR ABSTRACT:"DT2216" OR TITLE:"DT-2216" OR ABSTRACT:"DT-2216" OR TITLE:"BCL-XL PROTAC DT2216" OR ABSTRACT:"BCL-XL PROTAC DT2216") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about DT2216, not a curated reading list.
Shares BCL-2 inhibitors, PROTACs & molecular glues (targeted protein degradation).
Shares BCL-2 inhibitors, PROTACs & molecular glues (targeted protein degradation).
Shares PROTACs & molecular glues (targeted protein degradation), Ovarian cancer.
Shares PROTACs & molecular glues (targeted protein degradation), Ovarian cancer.
Shares PROTACs & molecular glues (targeted protein degradation), Ovarian cancer.
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