ArticleMolecular cancer therapeutics2023
Targeting RET Solvent-Front Mutants with Alkynyl Nicotinamide-Based Inhibitors.
Article in Molecular cancer therapeutics, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
7 citing papers in PubMed, 12 citations in OpenAlex.
- Synthesis, and evaluation of novel low nanomolar isoindigo-based RET kinase inhibitors.RSC advances · 2026Article
- Advances in Targeted Therapy for Non-Small-Cell Lung Cancer: Current Progress and Future Directions.International journal of molecular sciences · 2025Review
- Identification of alkynyl nicotinamide HSN748 as a RET solvent-front mutant inhibitor with intracranial efficacy.RSC medicinal chemistry · 2025Article
- Review
- Targeting Oncogenic RET Kinase by Simultaneously Inhibiting Kinase Activity and Degrading the Protein.Journal of medicinal chemistry · 2025Article
- Identification and characterization of a potent and selective HUNK inhibitor for treatment of HER2+ breast cancer.Cell chemical biology · 2024Article
- Adaptive Darwinian off-target resistance mechanisms to selective RET inhibition in RET driven cancer.NPJ precision oncology · 2024Article
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Authors and funding
11 authors at 3 institutions in 1 country.
Funding
Abstract
Selpercatinib (LOXO292) and pralsetinib (BLU667) are RET protein tyrosine kinase inhibitors (TKIs) recently approved for treating RET-altered cancers. However, RET mutations that confer selpercatinib/pralsetinib resistance have been identified, necessitating development of next-generation RET TKIs. While acquired RET G810C/R/S/V mutations were reported in selpercatinib-treated patients, it was unclear whether all of these and other potential G810 mutants are resistant to selpercatinib and pralsetinib. Here, we profiled selpercatinib and pralsetinib on all six possible G810 mutants derived from single nucleotide substitution and developed novel alkynyl nicotinamide-based RET TKIs to inhibit selpercatinib/pralsetinib-resistant RET G810 mutants. Surprisingly, the G810V mutant found in a clinical study was not resistant to selpercatinib or pralsetinib. Besides G810C/R/S, G810D also conferred selpercatinib/pralsetinib resistance. Alkynyl nicotinamide compounds such as HSN608, HSL476, and HSL468 have better drug-like properties than alkynyl benzamides. Six of these compounds inhibited all six G810 solvent-front mutants and the V804M gatekeeper mutant with IC50 < 50 nmol/L in cell culture. Oral administration of HSN608 at a well-tolerated dose (30 mg/kg) gave plasma level > 30x the IC50s of inhibiting all G810 mutants in cell culture. In cell-derived xenograft tumors driven by KIF5B-RET (G810C) that contains the most frequently observed solvent-front mutant in selpercatinib-treated patients, HSN608, HSL476, and HSL468 significantly suppressed and caused regression of the selpercatinib-resistant tumors. This study clarifies the sensitivities of different RET solvent-front mutants to selpercatinib and pralsetinib and identifies novel alkylnyl nicotinamide-based RET TKIs for inhibiting selpercatinib/pralsetinib-resistant G810 mutants.
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