P2, N=50, Completed, Dana-Farber Cancer Institute | Active, not recruiting --> Completed

However, we recently developed a PCNA inhibitor, AOH1996, which acts as a molecular glue between PCNA and RNA Pol II promoting selective killing of cancer cells through the induction of transcription-replication conflicts. We coupled artificial intelligence-based computational screens with thermal shift assays in a search for novel hit compounds, and characterized a key hit through protein crystallography, a cellular thermal shift assay and protein frustration calculations. Notably, we discovered that the Hsp90α inhibitor, SNX-2112, binds to PCNA within the major PIP-box binding pocket, revealing a new chemical scaffold for the potential development of novel PCNA-targeting inhibitors.

Methods Four HSP90 inhibitors (TAS-116, XL-888, SNX-2112, 17-AAG) were tested at each compound's cell-specific LC50 in HT1080 (linear and circular HACs) and HEK293 (linear HAC) cells, with GRN163L as a positive control. Conclusions TAS-116 consistently disrupts telomere maintenance-driving linear HAC loss, telomere shortening, reduced FISH signal, elevated TIFs, and increased MNi-thereby validating the HAC-based framework for discriminating telomere-directed activity. These findings support the therapeutic promise of HSP90 inhibition against telomere maintenance in cancer.

P1/2, N=64, Suspended, National Cancer Institute (NCI) | Trial completion date: Dec 2026 --> Dec 2027 | Recruiting --> Suspended | Trial primary completion date: Feb 2026 --> Dec 2026

We developed NN-01-195 as a novel chimeric small molecule that combines an AURKA inhibitor related to TAS-119/VIC-1911 with an HSP90-binding moiety related to SNX2112, and evaluated its function. Further, in combination with an inhibitor of the G2/M checkpoint protein WEE1, NN-01-195 is more potent than VIC-1911 in limiting growth of xenograft tumors. These data support the exploration of NN-01-195 and improved analogs as promising new candidates for therapeutic evaluation.

P1, N=78, Active, not recruiting, Taiho Pharmaceutical Co., Ltd. | Trial completion date: Dec 2025 --> Dec 2026 | Trial primary completion date: Dec 2025 --> Dec 2026 | Recruiting --> Active, not recruiting

NIR irradiation induces pyroptosis via caspase-3/GSDME activation and immunogenic cell death, while Ganetespib suppresses glycolysis (HK2/PKM2 downregulation) to reverse lactate-driven immunosuppression. This dual-action strategy synergistically enhances T-cell infiltration and ablates residual/metastatic lesions, offering a transformative approach for unresectable Osteosarcoma.

P1, N=63, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Dec 2025 --> Dec 2026 | Trial primary completion date: Dec 2025 --> Dec 2026

Here, we study EV secretion from individual breast cancer cells and the changes under treatment with the HSP90-inhibiting cancer drug tanespimycin (17AAG)...Moreover, our results emphasize that using CD63 as the sole EV capture protein may hide important EV subpopulations. Overall, our platform may support future choices of EV biomarkers for diagnostic and biomedical purposes and help in understanding the heterogeneous drug response of cancer cells.

Paired liver biopsies revealed no significant changes across treatment groups. While the combination of XL888 and pembrolizumab was safe and induced systemic immune modulation, limited clinical efficacy was observed and did not impact the PDAC TME.

A critical unanswered question remains: which form of the dual inhibitions caused the observed toxicity in humans that led to the spectacular failure of the trials and which underlies the limited efficacy that might be the real reason for the only approval of the orally administered ATP-binding inhibitor, Pimitespib (TAS-116), in 2022 by Japan? We suggest that addressing this question could prompt a paradigm shift in the design of next-generation anti-Hsp90 cancer therapeutics.

P1, N=26, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Nov 2025 --> Nov 2026