The natural compound KH617: A safe and selective therapeutic agent targeting GBM metabolic reprogramming

Glycolysis is a critical energy metabolic pathway in tumors, providing both energy and essential building blocks for proliferation. Tumors often reprogram their metabolic profile to enhance glycolytic capacity. Prior efforts to target tumor metabolism have frequently failed due to significant systemic side effects. Leveraging synthetic biology approaches, we have developed KH617, a first-in-class small molecule, which demonstrates the ability to modulate tumor glycolysis by concurrently targeting multiple key enzymes overexpressed in glioblastoma (GBM), including phosphofructokinase-1 (PFK1) and phosphofructokinase-2 (primarily via PFKFB3). This multi-target modulation inhibits GBM growth. KH617's unique mechanism of action allows for selective inhibition of malignant cells while sparing normal cells, such as astrocytes. Preliminary clinical data from Phase I trials have confirmed a favorable safety profile and encouraging early anti-GBM activity, consistent with preclinical findings. As of 30 June 2024, 24 participants with histologically confirmed, treatment-refractory advanced solid tumors (including 22 recurrent high-grade gliomas and 2 other advanced solid tumors) were enrolled in the study across five dose cohorts: 5, 10, 17, 25, and 33 mg/kg. No dose-limiting toxicities (DLTs) or treatment-related serious adverse events (TRSAEs) were observed during the study. A single patient experienced two grade ≥3 treatment-related adverse events (TRAEs) - leukopenia and neutropenia - which resolved within two days. Most TRAEs of KH617 are manageable laboratory or electrocardiograpy abnormalities with less severity. Partial responses (PR) were observed in two patients (one recurrent glioblastoma and one recurrent anaplastic astrocytoma) within the 33 mg/kg cohort, which was confirmed as the recommended Phase II dose (RP2D), with target lesion reductions of 96.99% and 97.06%, respectively. 33 mg/kg cohort demonstrated the best clinical benefit, with an expected mOS of > 18 months. Encouraged by KH617's favorable safety profile and promising early anti-tumor activity in patients with recurrent glioma, we are advancing this compound into a Phase II clinical trial for patients with recurrent GBM (NCT07138001). Beyond GBM, ongoing research is exploring the potential of KH617 across a broader spectrum of human tumor types.