{"entity":{"id":"dt2216","kind":"drug","name":"DT2216","aka":["DT-2216","BCL-XL PROTAC DT2216"],"tldr":"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.","summary":"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.\n\nThe 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).","status":"phase-2","asOf":"2026-11-03","links":[{"label":"Dialectic Therapeutics","url":"https://www.dialectictherapeutics.com/"},{"label":"Khan et al. 2019, Nature Medicine: a selective BCL-XL PROTAC degrader achieves safe and potent antitumour activity","url":"https://doi.org/10.1038/s41591-019-0668-z"},{"label":"Mahadevan et al. 2025, Journal of Hematology and Oncology: first-in-human phase 1 study of DT2216 in relapsed or refractory solid malignancies","url":"https://doi.org/10.1186/s13045-025-01753-8"},{"label":"NCI Thesaurus C179922","url":"https://ncit.nci.nih.gov/ncitbrowser/ConceptReport.jsp?dictionary=NCI_Thesaurus&code=C179922"},{"label":"ClinicalTrials.gov: NCT04886622 (phase 1)","url":"https://clinicaltrials.gov/study/NCT04886622"},{"label":"ClinicalTrials.gov: NCT06620302 (fibrolamellar carcinoma and solid tumours)","url":"https://clinicaltrials.gov/study/NCT06620302"},{"label":"ClinicalTrials.gov: NCT06964009 (platinum-resistant ovarian cancer)","url":"https://clinicaltrials.gov/study/NCT06964009"}],"tags":[],"related":[],"cancers":["ovarian"],"sections":[],"technologies":["protac-degrader","bcl2-inhibitors"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"code":"DT2216","modality":"small molecule (PROTAC degrader)","mechanism":"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.","approvals":[],"mechanismSteps":["One end of DT2216 binds BCL-XL, a protein that keeps cancer cells alive","The other end recruits the VHL ubiquitin ligase","BCL-XL is tagged and destroyed by the proteasome","Cancer cells that depend on BCL-XL die; platelets, which have little VHL, are largely spared"],"toxicity":[],"access":[],"regulatoryEvents":[]},"route":"/drugs/dt2216/","neighbours":{"cancer":[{"id":"ovarian","kind":"cancer","name":"Ovarian cancer","route":"/cancers/ovarian/"}],"technology":[{"id":"bcl2-inhibitors","kind":"technology","name":"BCL-2 inhibitors","route":"/technologies/bcl2-inhibitors/"},{"id":"protac-degrader","kind":"technology","name":"PROTACs & molecular glues (targeted protein degradation)","route":"/technologies/protac-degrader/"}]}}