LBPO.CH01 · 化学 · Late-Breaking
生物合成来源分子KHN705的广谱抗肿瘤活性
Broad-spectrum antitumor activity of the biosynthetically derived molecule KHN705
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
引言：天然产物及其衍生物是化疗药物和抗体药物偶联物（ADC）的关键有效载荷。我们此前通过生物合成技术开发了KH617，一种靶向肿瘤代谢重编程的小分子。KH617目前正处于II期临床试验（NCT07138001），评估其作为胶质母细胞瘤潜在疗法的疗效和安全性。在此，我们报告天然产物KHN705的广谱抗肿瘤活性。KHN705在包括胃癌、肝细胞癌、肺癌和脑癌在内的多种人类癌症类型中表现出与单药化疗相当的疗效，支持其进一步开发用于治疗多种恶性肿瘤。
方法：体外：孵育72小时后，测定其对14种人类癌细胞系（急性髓系白血病；结直肠癌[顺铂和5-FU耐药变体]；淋巴瘤；膀胱癌；乳腺癌；胃癌；前列腺癌；子宫内膜癌；甲状腺癌；食管癌；宫颈癌；脑癌；肾细胞癌；肺癌）的IC50值。使用CellTiter-Glo发光法评估细胞毒性。体内：使用NCI-N87-Luc（胃癌）、Hep3B-luc（肝细胞癌）、NCI-H460（肺癌）和U87MG-Luc（脑癌）细胞系建立原位模型。小鼠接受赋形剂或药物（KHN705、紫杉醇、瑞戈非尼、培美曲塞钠、替莫唑胺）治疗，持续时间为16至28天。通过生物发光成像（BLI，光子/秒）评估肿瘤负荷。安全性：在小鼠中进行了14天口服毒性研究。评估了脏器系数和心脏组织病理学。
结果：体外：KHN705在所有14种受试人类癌细胞系中均表现出广谱抗肿瘤活性。值得注意的是，它在顺铂和5-FU耐药细胞系中表现出与母体化合物相当的疗效，提示其可能成为化疗耐药患者的潜在治疗选择。体内：在胃癌、肝细胞癌、肺癌和脑癌的原位CDX模型中，KHN705表现出与单药化疗相当的抗肿瘤活性。安全性和药代动力学：KHN705的最大耐受剂量（MTD）为2 g/kg。口服生物利用度约为20%，与静脉给药相比，胃组织中的Cmax和AUC显著更高，且半衰期延长。
结论：我们首次证明了KHN705的抗肿瘤活性，这得益于我们的生物合成技术。KHN705有望成为化疗耐药肿瘤患者的治疗选择，尤其是胃癌，其在胃组织中的优先分布可能带来更强的获益。
查看英文原文 English abstract
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.
利益披露 Disclosure
Y. Feng,
Sichuan Honghe Biotechnology Co., Ltd. No. 108, Shuxi East Road, Jinniu District, Chengdu, Sichuan, China Employment.
Biotechnology Innovation Drug Application and Transformation Key Laboratory of Sichuan Province, Chengdu, China ).
W. Mao,
Sichuan Honghe Biotechnology Co., Ltd. No. 108, Shuxi East Road, Jinniu District, Chengdu, Sichuan, China Employment.
Y. Yuan,
Sichuan Honghe Biotechnology Co., Ltd. No. 108, Shuxi East Road, Jinniu District, Chengdu, Sichuan, China Employment.
H. Chen,
Sichuan Honghe Biotechnology Co., Ltd. No. 108, Shuxi East Road, Jinniu District, Chengdu, Sichuan, China Employment.
Q. Tang,
Sichuan Honghe Biotechnology Co., Ltd. No. 108, Shuxi East Road, Jinniu District, Chengdu, Sichuan, China Employment.
Y. Zhu,
Sichuan Honghe Biotechnology Co., Ltd. No. 108, Shuxi East Road, Jinniu District, Chengdu, Sichuan, China Employment.
H. Luo,
Sichuan Honghe Biotechnology Co., Ltd. No. 108, Shuxi East Road, Jinniu District, Chengdu, Sichuan, China Employment.
Biotechnology Innovation Drug Application and Transformation Key Laboratory of Sichuan Province, Chengdu, China ).
M. Zhao,
Sichuan Honghe Biotechnology Co., Ltd. No. 108, Shuxi East Road, Jinniu District, Chengdu, Sichuan, China Employment.
Biotechnology Innovation Drug Application and Transformation Key Laboratory of Sichuan Province, Chengdu, China ).
Chengdu Kanghong Pharmaceuticals Group Co. Ltd, Chengdu, China Employment.
X. Ke,
Sichuan Honghe Biotechnology Co., Ltd. No. 108, Shuxi East Road, Jinniu District, Chengdu, Sichuan, China Employment.
Biotechnology Innovation Drug Application and Transformation Key Laboratory of Sichuan Province, Chengdu, China ).
Chengdu Kanghong Pharmaceuticals Group Co. Ltd, Chengdu, China Employment.