Gavreto (pralsetinib)

Using two mouse studies that model multi-organ metastases and breast tumor formation in the brain, we observed that RET inhibition significantly prevented the circulating tumor cells from forming brain metastases and suppressed the growth of intracranially implanted tumor cells, but did not significantly inhibit the progression of well-established brain metastases. Together, our findings demonstrated that RET is highly activated in BCBM and functioning as a novel mediator of BCBM, and that RET plays a new role as a viable therapeutic target for BCBM.

Selpercatinib and pralsetinib are the most frequently studied RET inhibitors. Notably, research on next-generation RET inhibitors as monotherapy approaches (e.g., LOXO-260, enbezotinib, SY-5007 and TY-1091) is currently underway...While selective RET inhibitors have demonstrated therapeutic potential, concerns regarding drug resistance and toxicity persist. Therefore, future strategies should prioritize the development of next-generation inhibitors and the optimization of combination regimens to improve outcomes for RET-altered thyroid cancer patients.

Herein, we report a series of compounds featuring a novel piperazine-amide scaffold, designed and synthesized from BLU-667 via sequential bioisosteric replacement, linkage truncation, and subsequent structure-activity relationship (SAR) optimization...Furthermore, it exhibited favorable oral pharmacokinetic properties in mice, demonstrating superior in vivo efficacy compared to the multikinase inhibitor cabozantinib. In conclusion, compound 13 is a promising preclinical candidate.

Incorporating targeted therapy with surgery and tailored adjuvant treatment may lead to durable remission in selected patients with locally advanced disease. Prospective studies need to be conducted to further define the treatment sequencing and validate this multi-modal approach.

This case expands the current understanding of RET fusion partners and raises important questions regarding the functional and therapeutic implications of non-canonical fusions. It underscores the necessity of corroborating DNA-level findings with RNA and/or protein expression data and highlights the limitations of existing RET-targeted therapies for atypical RET fusions that may lack an intact kinase domain.

The clinical therapeutic benefits of the second-generation RET inhibitor pralsetinib are greatly compromised by acquired resistance mediated by solvent-front mutations (e.g., RETG810R/S/C)...However, the relatively poor pharmacokinetic properties of these compounds will limit their further development. Therefore, compound 7qe might be a promising lead compound for the development of novel RETV804M and RETG810C inhibitors overcoming the clinical acquired resistance.

P2, N=99, Recruiting, Genentech, Inc. | Trial completion date: Mar 2029 --> May 2030 | Trial primary completion date: Dec 2025 --> Nov 2026

2 weeks later, the corneal findings improved and visual acuity increased. The patient was much better 1 months later.DiscussionThis case report describes corneal edema with epithelial defect as a rare side effect of pralsetinib and highlights the importance of collaboration between oncologists and ophthalmologists.

Traditional multi-kinase inhibitors (MKIs, such as cabozantinib and vandetanib) exhibit significant side effects due to non-selective inhibition of targets like VEGFR, and also suffer from resistance associated with RET mutations (e.g., V804L/M, G810C/S/R), both of which limit their clinical application...To overcome drug resistance, the design strategies of novel inhibitors focus on multi-target inhibition (such as PLM-101 targeting RET/YES1/FLT3, TPX-0046 targeting RET/SRC), structural optimization (such as helical ring derivatives enhancing binding stability), and natural compound screening (such as ZINC series molecules)...For instance, selpercatinib combined with crizotinib can inhibit MET amplification-driven resistance, while arsenic trioxide combined with pralsetinib restores sensitivity by inhibiting the HH-Gli pathway. Current clinical trials show that novel RET inhibitors such as SY-5007 have a significant objective response rate in advanced RET fusion-positive non-small cell lung cancer and are safer than traditional drugs. In the future, it is necessary to further develop broad-spectrum mutation coverage and highly selective inhibitors, and explore individualized combination treatment regimens to improve prognosis. This article systematically reviews the progress, resistance mechanisms and coping strategies of RET-targeted therapy, providing a theoretical basis and direction for the development of precision anti-cancer drugs.

P4, N=800, Recruiting, Fudan University | N=200 --> 800 | Trial completion date: Apr 2027 --> Dec 2028 | Trial primary completion date: Apr 2026 --> Dec 2026

RET-selective kinase inhibitors (selpercatinib, pralsetinib) are in current clinical use for RET-driven tumors. We sought to exploit the event-driven pharmacology of targeted protein degradation to achieve pan-mutant activity against RET-driven cancers with a single selective RET degrader, while utilizing non-phthalimide cereblon (CRBN) ligands to discover orally bioavailable heterobifunctional degraders. Here we describe the medicinal chemistry efforts that led to compound 20, an orally bioavailable, brain-penetrant, pan-mutant and pan-fusion RET heterobifunctional degrader.

Multikinase inhibitors such as vandetanib and cabozantinib were the first few effective inhibitors which have been shown to slow disease progression in the treatment of advanced MTC. In more recent years, these have been followed by highly-selective RET inhibitors selpercatinib and pralsetinib which have made their way into the clinic, demonstrating high efficacy and a more favourable side-effect profile due to their reduction in off-target effects. In spite of these successes, there remains a continued need to develop strategies to overcome treatment resistance.