DT2216

Collectively, our findings suggest that the combination of DT2216/everolimus potentiates the anti-tumor efficacy of MRTX1133 associated with enhanced apoptosis induction and inhibition of compensatory survival signaling.

The HBPROTAC system consists of two components: (1) Tz-PU, a tetrazine-conjugated HSP90 inhibitor designed for tumor-selective accumulation, and (2) TCO-caged PROTAC prodrugs (TCO-MZ1 or TCO-DT2216), which release active PROTACs (MZ1 or DT2216) through inverse electron demand Diels-Alder (IEDDA) reactions with Tz-PU...Moreover, inhibition by Tz-PU synergistically enhanced the degradation efficiency of the target proteins through HSP90-mediated signaling. The tumor-specific and enhanced degradation character of HBPROTAC was confirmed in various tumor cell lines and the melanoma mouse model, demonstrating that this strategy establishes a broadly applicable platform for tumor-specific spatiotemporal control of targeted protein degradation and diminished off-tissue on-target toxicity.

These findings establish XZ739 as a promising therapeutic candidate for BCL-XL-dependent CCA, highlighting its translational potential for rational combination with chemotherapy to overcome resistance while mitigating hematologic toxicity.

KRAS inhibitors, including KRAS G12D inhibitor MRTX1133, are promising therapeutics against KRAS-mutated pancreatic ductal adenocarcinoma (PDAC), but drug resistance limits their efficacy. Our study reveals that robust induction of apoptosis using a combination of BCL-xL PROTAC degrader and an mTOR inhibitor, significantly enhances MRTX1133 efficacy in PDAC models without increasing toxicity to normal tissues.

Our findings provide new insights for combination therapy including Bcl-xL degradation for melanoma treatment.

Based on the rapid recovery of transient thrombocytopenia that occurred only in the first cycle and the degradation of BCL-XL in peripheral leukocytes, the RP2D of DT2216 is 0.4 mg/kg IV BIW. (NCT04886622).

Interestingly, inhibition of BCL-XL in doxorubicin-persistent OXPHOS-high TNBC cells rapidly abrogated mitochondrial elongation and respiratory function, followed by caspase 3/7 activation and cell death. The platelet-sparing proteolysis-targeted chimera (PROTAC) BCL-XL degrader DT2216 enhanced the efficacy of doxorubicin against TNBC xenografts in vivo without induction of thrombocytopenia that is often observed with the first-generation BCL-XL inhibitors, supporting the development of this combinatorial treatment strategy for eliminating dormant tumor cells that persist after treatment with anthracycline-based chemotherapy.

Interestingly, inhibition of BCL-XL in doxorubicin-persistent OXPHOS-high TNBC cells rapidly abrogated mitochondrial elongation and respiratory function, followed by caspase 3/7 activation and cell death. The platelet-sparing proteolysis targeted chimera (PROTAC) BCL-XL degrader DT2216 enhanced the efficacy of doxorubicin against TNBC xenografts in vivo without induction of thrombocytopenia that is often observed with the first-generation BCL-XL inhibitors, supporting the development of this combinatorial treatment strategy for eliminating dormant tumor cells that persist after treatment with anthracycline-based chemotherapy.

We combined A-1331852 and S63845 with IKE or RSL3 (ferroptosis-inducing drugs). These data indicate that BCL-xL maintains ChRCC cell survival by suppressing apoptosis. The BCL-xL-specific PROTAC DT2216, currently in clinical trials, may provide an opportunity for ChRCC therapy.

The combination of DHODH inhibition with Brequinar and BCL-XL degradation by DT2216, a proteolysis targeting chimera (PROTAC), significantly inhibits PDAC tumor growth. These data define mechanisms of adaptation to DHODHi and support combination therapy targeting BCL-XL in PDAC.

In HGSOC xenografts, targeted degradation of BCL-XL using the platelet-sparing proteolysis-targeting chimera (PROTAC) DT2216 matches the efficacy of paclitaxel monotherapy while avoiding the chronic thrombocytopenia induced by BCL-XL inhibitors such as navitoclax (ABT-263). Moreover, DT2216 treatment blunts the rapid apoptotic adaptation caused by other BCL-X L inhibitors, indicating that targeted degradation of pro-survival proteins may yield more durable responses than inhibition alone. These findings uncover a mechanistic framework for safely exploiting the apoptotic dependency convergence caused by mitotic arrest and substrate detachment and support the clinical development of BCL-XL-targeting PROTACs to overcome chemoresistance in ovarian cancer and other solid tumors.

P1/2, N=81, Recruiting, Children's Oncology Group | Initiation date: Feb 2026 --> Jun 2025