RET V804*

Kinase profiling revealed moderate selectivity, with off-target activity mainly restricted to a limited group of receptor tyrosine kinases. These results support CN-3 as a promising lead for next-generation RET-targeted therapies.

These findings identify compound 4c as an early lead with promising biochemical potency in this initial exploration of isoindigo-based RET inhibitors. However, it should be noted that these results are based on biochemical (enzymatic) assays only, and further cell-based validation is required to assess the translational potential of this compound.

Histopathology confirmed multifocal PTC and a background of chronic lymphocytic thyroiditis with 23 lymph nodes negative for metastasis. This case presents heterogeneity of oncogenic drivers in PTC and the potential value of comprehensive molecular profiling in risk stratification and management.

In addition, 9 exhibited remarkable antitumor activity at a dose of 10 mg/kg/day, indicating that it completely hindered the growth of tumors induced by BAF3-KIF3B-RET-WT xenografts. In summary, 9 can be demonstrated to act as a potential RET inhibitor, as well as a treatment for RET-related cancers.

GCs with a preoperative bCTN between 12.6 and 28.3 ng/L have a very high probability of achieving complete biochemical and structural remission after surgery, even when a small intrathyroidal MTC is already present and independently from the RET germline mutation.

RET pathogenic variants V804M, K666N, and C609Y were the most identified variants, particularly through broad panel testing, indicating increased incidental diagnosis of MEN2. The identification of previously unlisted variants underscores the need for dynamic guideline updates and ongoing curation to optimize clinical management of RET pathogenic variant carriers.

Collectively, BYS10 represents a novel, highly selective RET inhibitor with superior in vitro and in vivo activity against multiple RET alterations compared to Selpercatinib. Its recent Investigational New Drug (IND) approvals from the FDA and NMPA underscore its therapeutic potential for RET-driven malignancies.

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.

Optimized pharmacokinetic properties (38.9% oral bioavailability in monkey) and central nervous system penetration support clinical translation. APS03118 is currently in phase Ib trials (NCT05653869) for patients progress on first-generation SRIs, offering a promising strategy to address acquired resistance.

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.

The prevalence of MEN2 and PHTS is ∼10-20 times higher than it is currently estimated for the general population. Most affected individuals are not diagnosed with thyroid cancer. Our findings may change the clinical approach to patients with moderate-risk RET mutations.

In 2020, two selective RET inhibitors, selpercatinib and pralsetinib were approved by the US FDA. However, the poor solubility of these compounds will limit their further development. Therefore, compound 8w and 8s might be promising lead compounds for the development of novel RETV804M and RETG810C inhibitors overcoming the clinically acquired resistance.