LBPO.CH01 · 化学 · Late-Breaking
天然化合物KH617：一种靶向GBM代谢重编程的安全且选择性的治疗药物
The natural compound KH617: A safe and selective therapeutic agent targeting GBM metabolic reprogramming
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
糖酵解是肿瘤中一条关键的能量代谢途径，为增殖提供能量和必需的组成成分。肿瘤常常重编程其代谢特征以增强糖酵解能力。此前靶向肿瘤代谢的努力常因显著的全身副作用而失败。利用合成生物学方法，我们开发了KH617，一种首创（first-in-class）的小分子，它能够通过同时靶向胶质母细胞瘤（GBM）中过表达的多个关键酶（包括磷酸果糖激酶-1（PFK1）和磷酸果糖激酶-2（主要通过PFKFB3））来调控肿瘤糖酵解。这种多靶点调控抑制了GBM的生长。KH617独特的作用机制使其能够选择性地抑制恶性细胞，同时不损害正常细胞（如星形胶质细胞）。I期试验的初步临床数据已证实其良好的安全性特征和令人鼓舞的早期抗GBM活性，与临床前发现一致。截至2024年6月30日，共有24名经组织学确诊、治疗难治的晚期实体瘤参与者（包括22例复发性高级别胶质瘤和2例其他晚期实体瘤）在五个剂量队列（5、10、17、25和33 mg/kg）中入组研究。研究期间未观察到剂量限制性毒性（DLT）或治疗相关严重不良事件（TRSAE）。一名患者经历了两次≥3级治疗相关不良事件（TRAE）——白细胞减少和中性粒细胞减少——均在两天内缓解。KH617的大多数TRAE是可控的实验室或心电图异常，严重程度较轻。在33 mg/kg队列中，两名患者（一例复发性胶质母细胞瘤和一例复发性间变性星形细胞瘤）观察到部分缓解（PR），该队列被确认为推荐II期剂量（RP2D），靶病灶分别缩小96.99%和97.06%。33 mg/kg队列展现出最佳临床获益，预期mOS >18个月。受KH617良好的安全性特征以及在复发性胶质瘤患者中令人鼓舞的早期抗肿瘤活性的鼓舞，我们正在推进该化合物进入针对复发性GBM患者的II期临床试验（NCT07138001）。除GBM外，正在进行的研究正在探索KH617在更广泛的人类肿瘤类型中的潜力。
查看英文原文 English abstract
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.
利益披露 Disclosure
C. Li,
Sichuan Honghe Biotechnology Co., Ltd. No. 108, Shuxi East Road, Jinniu District, Chengdu, Sichuan, China Employment.
X. Yang,
Sichuan Honghe Biotechnology Co., Ltd. No. 108, Shuxi East Road, Jinniu District, Chengdu, Sichuan, China Employment.
L. Liu,
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 ).
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 ).
L. Lin,
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.
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.
Z. Kang,
Department of Neuro-oncology, Cancer Center, Beijing Tiantan Hospital, Capital Medical University, Beijing, China Employment.
W. Li,
Department of Neuro-oncology, Cancer Center, Beijing Tiantan Hospital, Capital Medical University, Beijing, 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.