DT2216
DT2216, VHL-recruiting PROTAC degrader of BCL-xL
Written by Aaron CuhaReviewed Sep 2026
Also known as: DT-2216
The engineered answer to the navitoclax platelet problem: a degrader that hands BCL-xL to an E3 ligase platelets barely express. In the first human trial, 20 patients with solid tumours, only one dose-limiting toxicity occurred, a grade 4 thrombocytopenia that resolved within 48 hours.
Overview
Navitoclax kills senescent cells and platelets through the same target. DT2216 was designed around that. It is a proteolysis-targeting chimera, a bifunctional molecule that links a navitoclax-derived BCL-xL binder to a ligand for the Von Hippel-Lindau E3 ubiquitin ligase, so that BCL-xL is tagged for destruction rather than merely inhibited. The platelet-sparing logic is specific and testable: platelets express very little VHL, so the degrader should spare them.
In mice and human cell lines this worked as designed. The 2019 Nature Medicine paper reported DT2216 was less toxic to platelets than ABT-263 in vitro while being more potent against BCL-xL-dependent cancer cells, and inhibited growth of several xenograft tumours in mice without appreciable thrombocytopenia.
The first-in-human phase 1 published in 2025 tested intravenous DT2216 twice weekly in 20 patients with relapsed or refractory solid tumours at 0.04 to 0.4 mg/kg, median age 60.5, 60 percent female. There was one dose-limiting toxicity, a grade 4 thrombocytopenia that resolved within 48 hours; the lowest first-cycle platelet count ranged from 24,000 to 297,000, and in every case platelets recovered above 50,000 within four days. Stable disease was seen in 20 percent of patients, median overall survival was 7.9 months, and the recommended phase 2 dose was set at 0.4 mg/kg. Registry status in September 2026: that trial completed, an ovarian cancer combination trial is recruiting, and a Children's Oncology Group phase 1/2 is SUSPENDED with the reason given as unacceptable toxicity.
No ageing or senescence indication is registered for DT2216 anywhere. No senolytic has improved a clinical outcome in a randomised trial in humans, and every DT2216 trial is in cancer.
Mechanism of action
Established in human cell lines and mice, with the intended platelet sparing now supported by human phase 1 data: DT2216 binds BCL-xL and recruits the VHL E3 ubiquitin ligase, marking BCL-xL for proteasomal degradation. Because VHL is minimally expressed in platelets, the degradation is inefficient there. Senescent cells that depend on BCL-xL die when it is removed, which is the senolytic rationale, demonstrated in mice and not in people. In the human trial, BCL-xL degradation was confirmed in peripheral leukocytes at the top dose.
Human evidence
One published first-in-human phase 1 in 20 patients with solid tumours, plus registry records for two further oncology trials. No human has received DT2216 for senescence or ageing, and no such trial is registered.
- Phase 1, 20 patients with relapsed or refractory solid tumours: one dose-limiting toxicity (grade 4 thrombocytopenia, resolved within 48 hours), no bleeding episodes, no treatment-emergent adverse events leading to death, stable disease in 20 percent, median overall survival 7.9 months. National Institutes of Health supported.
- BCL-xL degradation in peripheral leukocytes was rapid and sustained at 0.4 mg/kg, the recommended phase 2 dose.
- NCT06964009, DT2216 with paclitaxel in platinum-resistant ovarian cancer, phase 1, RECRUITING as of September 2026.
- NCT06620302, Children's Oncology Group phase 1/2, SUSPENDED, reason given as unacceptable toxicity.
What this does not tell you: Twenty patients with advanced cancer, dosed intravenously twice weekly, tell you about short-term platelet behaviour and tolerability in that population. They do not tell you whether senescent cells were cleared, because senescence was not measured, and they say nothing about what repeated dosing would do to a healthy older adult. The suspension of the paediatric trial for unacceptable toxicity is a reminder that platelet sparing is not the same as safety.
Reading the research record
DT2216 is the clearest case in this field of a rational fix to a mechanism problem being carried into people. The problem, stated in 2010, was that BCL-xL inhibition kills platelets. The fix, published in 2019, was to degrade BCL-xL through a ligase platelets barely express. The first human data, published in 2025, are consistent with the fix: a single dose-limiting thrombocytopenia that resolved in 48 hours, against 29 of 55 patients with grade 3 or 4 thrombocytopenia on navitoclax.
That is a pharmacology success, not a geroscience result. Every DT2216 trial is in cancer, no ageing indication is registered, and the senolytic case for it remains entirely in mice. A Children's Oncology Group trial is suspended for unacceptable toxicity, which belongs on the same page as the phase 1 tolerability finding.
The evidence, charted
Fig. 1 · evidence composition
4of 6 citations (67%) are in people
Counted from the citation list on this page. The Human count is the same number shown in the badge at the top. Both understate any literature larger than the sources we cite.
Fig. 2 · evidence over time
Evidence spans 5 distinct years, 2010 to 2026, counted from the citation list on this page.
Fig. 3 · legal status at a glance
US
Not approved
UK
Approved
AU
Approved
CA
Not approved
Approved in 2 of 4, prescription route in 0, not approved in 2. A jurisdiction's classification is a regulatory fact, not a verdict on the science; see Legal status below for the full text and any notes.
Fig. 4 · dose response
No human dose response curve exists
We draw this figure where the data supports it. For this compound in humans it does not, so the panel stays empty rather than borrowing an animal curve and implying it transfers.
Key studies & citations
- Human2025
First in human phase 1 study of DT2216, a selective BCL-xL degrader, in patients with relapsed/refractory solid malignancies
20 patients, median age 60.5, 60 percent female, dose escalation 0.04 to 0.4 mg/kg intravenously twice weekly. One dose-limiting toxicity, a grade 4 thrombocytopenia resolving within 48 hours; lowest first-cycle platelet count 24,000 to 297,000, recovery above 50,000 within four days in all cases. Stable disease in 20 percent, median overall survival 7.9 months. Recommended phase 2 dose 0.4 mg/kg. National Institutes of Health supported.
Journal of Hematology and Oncology - Human2026
A Study of DT2216 in Relapsed/Refractory Malignancies
Dialectic Therapeutics, phase 1, enrolment 20, status COMPLETED. This is the registration for the first-in-human study above. No results are posted on the registry record itself.
ClinicalTrials.gov - Human2026
Testing the Addition of DT2216 to Usual Chemotherapy (Children's Oncology Group)
Children's Oncology Group phase 1/2, estimated enrolment 81, status SUSPENDED. The registry gives the reason as unacceptable toxicity. Verified live September 2026 and reported here because suspensions are findings.
ClinicalTrials.gov - Animal2019
A selective BCL-X(L) PROTAC degrader achieves safe and potent antitumor activity
Human cell lines and mouse xenografts. DT2216 was less toxic to platelets than ABT-263 in vitro, more potent against BCL-xL-dependent cancer cells, and inhibited xenograft tumour growth in mice without appreciable thrombocytopenia. The design rationale is that VHL is poorly expressed in platelets.
Nature Medicine - Animal2020
DT2216, a Bcl-xL-specific degrader, is highly active against Bcl-xL-dependent T cell lymphomas
Cells and mice. Activity against BCL-xL-dependent T cell lymphoma models, extending the preclinical case for selective degradation over inhibition.
Journal of Hematology and Oncology - Human2010
Navitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: a phase 1 dose-escalation study
The comparison that explains why DT2216 exists. With navitoclax, grade 3 or 4 thrombocytopenia occurred in 29 of 55 patients and was dose-limiting, attributed by the authors to high-affinity BCL-xL inhibition in platelets.
The Lancet Oncology
Frequently asked questions
Has DT2216 been tested for ageing?
No. All three registered DT2216 trials are oncology trials. No ageing or senescence indication is registered anywhere as of September 2026.
Did the platelet-sparing design work in people?
In the first 20 patients it looked like it did. There was one dose-limiting grade 4 thrombocytopenia that resolved within 48 hours, and platelets recovered above 50,000 within four days in every case. For comparison, navitoclax produced grade 3 or 4 thrombocytopenia in 29 of 55 patients in its phase 1.
What does PROTAC mean?
A proteolysis-targeting chimera: one end binds the target protein, the other end binds a ubiquitin ligase, and the cell destroys the target rather than the drug simply blocking it. Here the ligase is VHL, chosen because platelets express very little of it.
Is DT2216 safe?
Too little is known. The 20-patient phase 1 reported no bleeding and no treatment-related deaths, but a Children's Oncology Group phase 1/2 is suspended with unacceptable toxicity given as the reason. Both facts are current as of September 2026.