Guided by a scaffold-hopping strategy based on G-749 (denfivontinib), a series of quinazoline-based derivatives was designed and synthesized to explore structure-activity relationships (SAR)...Mechanism studies indicated that W4 induced G0/G1 cell cycle arrest and apoptosis, accompanied by a reduction in intracellular reactive oxygen species levels and a loss of mitochondrial membrane potential. Collectively, these results identified W4 as a potent FLT3 inhibitor and provided valuable SAR insights for further scaffold optimization.

P3, N=223, Terminated, Hoffmann-La Roche | Completed --> Terminated; Early termination of the study resulted from organizational and commercial decisions that led to the discontinuation of pralsetinib's global marketing and development in all territories (excluding US and Greater China).

Selpercatinib conferred significant PFS benefit over SoC in treatment-naïve (1L) patients with RET-mutation-positive MTC, with inconclusive results in the ≥2L setting. Matching retrospective real-world data to prospective trial data is feasible. EC arms to single-arm trials may provide evidence supporting the evaluation of comparative effectiveness.

Furthermore, the review elaborates on the clinical efficacy of highly selective RET inhibitors (selpercatinib and pralsetinib), including their breakthroughs in pediatric patients and radioactive iodine-refractory cases. Primary and acquired resistance mechanisms (on-target mutations, bypass activation) and corresponding strategies (next-generation inhibitors, combination therapies) are also analyzed. By integrating recent advances in basic and clinical research, this review provides a comprehensive reference for the precision diagnosis and treatment, mechanistic investigation, and drug development for RET fusion-positive PTC.

P=N/A, N=25, Not yet recruiting, Fudan University

RET fusion-positive LUAD comprises biologically heterogeneous subsets defined by fusion partners. KIF5B-RET tend to occur at earlier stages, whereas non-KIF5B are more frequently associated with CDKN2A co-mutations and may derive greater benefit from selective RET inhibition. Immunochemotherapy demonstrates comparable efficacy regardless of fusion partner, highlighting the need for partner-specific therapeutic strategies in RET fusion-positive LUAD.

A combined strategy with continued osimertinib and addition of the selective RET inhibitor selpercatinib was pursued based on biological rationale; however, the short duration of combined treatment precluded a meaningful assessment of clinical benefit. This case highlights the importance of molecular reassessment at progression to identify rare but actionable resistance mechanisms that may significantly influence therapeutic strategy in EGFR-mutant NSCLC.

Although selective RET inhibitors such as selpercatinib and pralsetinib have been clinically approved, the emergence of resistance mutations limits their durable efficacy, underscoring the need for novel therapeutic modalities. We report the design and synthesis of the first RET-targeting HyTTD, compound B2, which achieves 91.4% degradation of CCDC6-RET fusion protein in TPC-1 cells at 10 μM within 48 h. These results not only validate hydrophobic tag tethering as a feasible strategy for RET degradation but also propose a new therapeutic direction for RET-driven cancers.

These findings provide new insights into the individualized treatment of RET + NSCLC patients and emphasize the importance of considering the overall health status of patients in treatment decisions.

This study provides critical insights into the established and potential adverse events associated with selpercatinib and pralsetinib. The findings offer valuable evidence to guide the clinical use of RET inhibitors.

Collectively, our findings suggest GlcN as a potential therapeutic agent for HCC and underscore its chemosensitizing potential when combined with lenvatinib. Given GlcN's established clinical safety, this combination offers a translatable strategy for HCC therapy.

The cytotoxicity and pro-apoptotic effects were significantly attenuated by the ROS scavenger NAC. These findings provide a solid preclinical foundation for the further development of this combination therapy and underscore the importance of the "computational prediction-mechanistic validation" strategy in advancing cancer drug discovery.