Abstract 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-1β production, a pro-carcinogenic factor within the tumor microenvironment. Lower IL-1β 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 Citation Format: Anna Maria Serwotka-Suszczak, Andrew Saunders, Krzysztofa Odrzywol, Robert Dyjas, Piotr Kowalczyk, Przemysław Glaza, Roman Pluta, Karolina Brodzik, Joanna Lis, Olga Makowska, Joanna Majkut, Martyna Mianowska, Paulina Rozborska, Anna Sawicka, Marta Sowała, Agata Śnieżewska, Katarzyna Kaczanowska, Jan Klajn, Grzegorz Statkiewicz, Arkadiusz Zając, Katarzyna Brach, Michał Biśta, Paweł Dobrzański, Sylvain Cottens, Michał Walczak. A phase 1 clinical trial of CT-01, a dual degrader of GSPT1 and NEK7, alone or in combination with everolimus for the treatment of hepatocellular carcinoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr CT053.
Serwotka-Suszczak et al. (Fri,) studied this question.