CT-01（一种GSPT1和NEK7双重降解剂）单药或联合依维莫司（everolimus）治疗肝细胞癌的1期临床试验

Targeted protein degradation (TPD) has transformed modern drug discovery by enabling modulation of previously “undruggable” proteins, creating new therapeutic opportunities for diseases with limited treatment options. Molecular glues, a subclass of TPD agents, selectively bind to E3 ubiquitin ligases and remodel their surface to promote ubiquitination and subsequent degradation of target proteins. Here, we report the preclinical characterization and clinical development plan for CT-01, a novel molecular glue that induces selective degradation of G1 to S phase Transition 1 (GSPT1) and NIMA related kinase 7 (NEK7) proteins for the treatment of hepatocellular carcinoma (HCC). GSPT1 degradation triggers the Integrated Stress Response (ISR) leading to apoptosis, while NEK7 depletion reduces IL-1beta production, a pro-carcinogenic factor within the tumor microenvironment. Lower IL-1beta levels enhance immune activation and contribute to the compound's antitumor efficacy. In preclinical studies, CT-01 demonstrated potent target engagement and cytotoxicity in cancer cell models, confirmed by western blotting for degradation of GSPT1 and NEK7. In vivo , CT-01 inhibited tumor growth in human HCC xenograft mouse models, displaying a favorable pharmacokinetic and pharmacodynamic profile. Combination studies revealed clear synergy between CT-01 and everolimus, further enhancing antitumor activity both in vitro and in vivo . A first-in-human, open-label, multicenter Phase 1 clinical trial of CT-01 was initiated in May 2025. The study includes dose escalation and dose expansion parts to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of CT-01 as monotherapy and in combination with everolimus in subjects with intermediate or advanced HCC who have progressed on or are intolerant to prior systemic therapy. Up to 77 subjects may be enrolled in Part 1 (monotherapy) and up to 64 in Part 2 (combination therapy). Presented results indicate that targeting GSPT1 and NEK7 proteins by induction of its degradation could represent a new and effective strategy for cancer treatment. CT-01, a molecular glue has just completed preclinical development, and its safety, pharmacokinetics, pharmacodynamics and preliminary efficacy will be evaluated in a phase 1 study commencing in 2025 - an open-labeled, dose escalation and dose expansion study of CT-01 as monotherapy and combination with everolimus in subjects with intermediate or advanced hepatocellular carcinoma. Interim clinical data from this study will be available at the time of presentation