Novel Miniaturized Drug Conjugate Leverages HSP90-driven Tumor Accumulation to Overcome PI3K Inhibitor Delivery Challenges to Solid Tumors

The PI3K pathway, frequently activated in cancer, plays a key regulatory role, making it an appealing target for drug development. However, achieving sufficient inhibition of PI3K signaling for effective tumor control at tolerable doses has proven challenging. HSP90, a chaperone protein overexpressed and activated in many tumors, offers a potential solution, as small-molecule ligands targeting HSP90 can remain in tumors up to 20 times longer than in normal tissues.

We propose that conjugating a PI3K inhibitor like copanlisib with an HSP90-targeting ligand could expand the narrow therapeutic window of PI3K inhibitors. To test this hypothesis, we developed a novel drug conjugate, T-2143, combining these components. In xenograft models, T-2143 demonstrated rapid and sustained tumor accumulation, leading to deep pathway inhibition and superior efficacy compared to copanlisib alone. Additionally, the selective delivery of T-2143, along with masking the inhibitor’s active site, mitigated a major side effect of copanlisib—hyperglycemia.

These findings show that leveraging the selective retention of HSP90-targeting ligands within tumors can enable precise delivery of PI3K inhibitors, achieving therapeutic efficacy while avoiding hyperglycemia in mice. This approach offers a promising drug delivery strategy, enhancing the therapeutic window through targeted tumor delivery and reduced toxicity.