# DT2216

Source: https://onco.cc/drugs/dt2216/  
OnCo record `dt2216` (Treatment). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

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).

## Fields

- Kind: Treatment
- Status: phase-2
- Last checked: 2026-11-03
- Also known as: DT-2216; BCL-XL PROTAC DT2216
- 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.

## Sources

- Dialectic Therapeutics: https://www.dialectictherapeutics.com/
- Khan et al. 2019, Nature Medicine: a selective BCL-XL PROTAC degrader achieves safe and potent antitumour activity: https://doi.org/10.1038/s41591-019-0668-z
- Mahadevan et al. 2025, Journal of Hematology and Oncology: first-in-human phase 1 study of DT2216 in relapsed or refractory solid malignancies: https://doi.org/10.1186/s13045-025-01753-8
- NCI Thesaurus C179922: https://ncit.nci.nih.gov/ncitbrowser/ConceptReport.jsp?dictionary=NCI_Thesaurus&code=C179922
- ClinicalTrials.gov: NCT04886622 (phase 1): https://clinicaltrials.gov/study/NCT04886622
- ClinicalTrials.gov: NCT06620302 (fibrolamellar carcinoma and solid tumours): https://clinicaltrials.gov/study/NCT06620302
- ClinicalTrials.gov: NCT06964009 (platinum-resistant ovarian cancer): https://clinicaltrials.gov/study/NCT06964009

## Connected records

- cancers: [Ovarian cancer](https://onco.cc/cancers/ovarian/)
- technologies: [BCL-2 inhibitors](https://onco.cc/technologies/bcl2-inhibitors/), [PROTACs & molecular glues (targeted protein degradation)](https://onco.cc/technologies/protac-degrader/)

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