Broad-spectrum antitumor activity of the biosynthetically derived molecule KHN705

Introduction: Natural products and their derivatives are key payloads for chemotherapeutic agents and antibody-drug conjugates (ADCs). We previously developed KH617, a small molecule targeting tumor metabolic reprogramming, via biosynthetic technology. KH617 is currently in Phase II clinical trials (NCT07138001) for efficacy and safety assessment as a potential therapy for glioblastoma. Here, we report the broad-spectrum anti-tumor activity of the natural product KHN705. KHN705 exhibited comparable efficacy to single-agent chemotherapy across a wide range of human cancer types, including gastric, hepatocellular, lung, and brain cancers, supporting its further development for treating diverse malignancies. Methods: In Vitro: IC50 values were determined against 14 human cancer cell lines (acute myeloid leukemia; colorectal cancer [cisplatin- and 5-FU-resistant variants]; lymphoma; bladder cancer; breast cancer; gastric cancer; prostate cancer; endometrial cancer; thyroid cancer; esophageal cancer; cervical cancer; brain cancer; renal cell carcinoma; lung cancer) following a 72-hour incubation. Cytotoxicity was assessed using the CellTiter-Glo luminescent assay. In Vivo : Orthotopic models were established using NCI-N87-Luc (gastric), Hep3B-luc (hepatocellular), NCI-H460 (lung), and U87MG-Luc (brain) cell lines. Mice received vehicle or drug (KHN705, paclitaxel, regorafenib, pemetrexed sodium, temozolomide) for durations ranging from 16 to 28 days. Tumor burden was assessed by bioluminescence imaging (BLI, photons/s). Safety: A 14-day oral toxicity study was conducted in mice. Organ coefficients and cardiac histopathology were evaluated. Results: In Vitro : KHN705 demonstrated broad-spectrum anti-tumor activity across all 14 human cancer cell lines tested. Notably, it exhibited comparable efficacy to the parent compound in cisplatin- and 5-FU-resistant cell lines, suggesting a potential therapeutic option for chemotherapy-resistant patients. In Vivo : KHN705 exhibited anti-tumor activity comparable to single-agent chemotherapy in orthotopic CDX models of gastric, hepatocellular, lung, and brain cancers. Safety and Pharmacokinetics: The maximum tolerated dose (MTD) of KHN705 was 2 g/kg. Oral bioavailability was approximately 20%, with significantly higher Cmax and AUC in gastric tissue compared to intravenous administration, and a prolonged half-life. Conclusion: We report the first demonstration of KHN705's anti-tumor activity, enabled by our biosynthetic technology. KHN705 holds promise as a therapeutic option for patients with chemotherapy-resistant tumors, particularly gastric cancer, where preferential gastric tissue distribution may confer enhanced benefit.