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Identification of alkynyl nicotinamide HSN748 as a RET solvent-front mutant inhibitor with intracranial efficacy

Ujjwol Khatri1,2, Neetu Dayal3, Kofi B Owusu4

  • 1Department of Pathology, University of Oklahoma Health Sciences Oklahoma City OK 73104 USA jie-wu@ouhsc.edu.

RSC Medicinal Chemistry
|June 11, 2025
PubMed

Insights

New alkynyl nicotinamide-based RET inhibitors show promise against resistant RET mutations and brain metastases in lung cancer. These compounds effectively target RET solvent-front mutations and demonstrate intracranial activity, offering a potential new therapeutic strategy.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • RET solvent-front mutations (G810C/R/S) confer resistance to approved RET protein tyrosine kinase inhibitors (TKIs) like selpercatinib and pralsetinib.
  • RET fusion-positive lung adenocarcinoma frequently develops brain metastases, necessitating treatments with intracranial activity.
  • There is a critical need for novel RET TKIs effective against resistant mutations and capable of penetrating the central nervous system (CNS).

Purpose of the Study:

  • To synthesize and evaluate novel alkynyl nicotinamide-based RET TKIs.
  • To assess the efficacy of these compounds against selpercatinib/pralsetinib-resistant RET solvent-front mutants (G810C/R/S) in vitro and in vivo.
  • To determine the intracranial activity and pharmacokinetic properties of promising candidates.

Main Methods:

  • Synthesis of alkynyl nicotinamide-based RET TKIs.
  • In vitro testing for inhibition of RET G810C/R/S mutants.
  • In vivo studies using cell-derived xenografts, transgenic mouse models (KIF5B-RET-induced lung tumors), and patient-derived xenografts (CCDC6-RET positive PDX).
  • Pharmacokinetic (PK) studies to measure drug concentrations in plasma and brain.

Main Results:

  • HSN748, HSND19, and HSND14 demonstrated potent inhibition of RET G810C/R/S mutants with low nanomolar IC50 values.
  • HSN748 induced regression of subcutaneous tumors without significant toxicity and reduced KIF5B-RET-driven lung tumors in mice.
  • HSN748 showed significant intracranial tumor inhibition in brain metastasis models and achieved a brain/plasma partition coefficient (Kp) of 0.4, indicating CNS penetration.

Conclusions:

  • Alkynyl nicotinamide-based RET TKIs, particularly HSN748, are effective against RET solvent-front mutations and resistant RET fusions.
  • HSN748 exhibits promising anti-tumor activity in both peripheral and central nervous system tumors.
  • These novel compounds represent a potential therapeutic strategy for patients with advanced RET-driven lung and thyroid cancers, including those with brain metastases.

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