Actinium‑225 NTSR1‑Targeted Radiopharmaceutical SKL35501

SKL35501 is an emerging radiopharmaceutical therapy that embodies much of what “next‑generation oncology” is supposed to mean: precise targeting, potent cell kill, and a built‑in companion diagnostic strategy. In January 2026, the US FDA cleared SKL35501 and its imaging partner SKL35502 for a phase 1 Investigational New Drug (IND).

SKL35501 originated as FL‑091, a small‑molecule radioligand vector developed to target neurotensin receptor 1 (NTSR1), a G‑protein–coupled receptor overexpressed in multiple solid tumors. Preclinical work showed that FL‑091 binds NTSR1 with high affinity and, when labeled with radionuclides such as lutetium‑177 or actinium‑225, achieves high tumor uptake with relatively fast clearance from normal tissues in xenograft models. In comparative studies, FL‑091 displayed improved binding and biodistribution over earlier NTSR1 ligands like 3BP‑227, translating into stronger tumor growth inhibition in several animal models.

Mechanistically, SKL35501 is designed to increase the accuracy of tumor targeting by exploiting the high expression of NTSR1 on cancer cells and using this receptor as a docking site for actinium‑225, a powerful alpha‑emitting isotope. After binding to NTSR1 on tumor cells, the ligand–isotope complex is internalized, allowing the decay of Ac‑225 to deliver extremely high‑energy alpha particles over a range of only a few cell diameters. Alpha emitters like Ac‑225 deposit dense ionization tracks and cause complex double‑strand DNA breaks, which are far more lethal to tumor cells than the damage caused by typical beta emitters, while the very short path length helps spare surrounding normal tissues. In preclinical studies, FL‑091‑based complexes achieved robust tumor uptake, rapid background clearance, and strong anti‑tumor activity across NTSR1‑positive xenograft models, supporting its advancement as a therapeutic vector. For SKL35501, those data underpin the expectation that combining FL‑091’s targeting profile with Ac‑225’s physics can deliver a highly potent, spatially confined radiation dose to otherwise resistant tumors.

NTSR1 itself is an attractive but relatively underexploited target in oncology. Preclinical and translational work has shown that NTSR1 is highly expressed in several difficult‑to‑treat cancers, including head and neck, colorectal, pancreatic, some breast cancers, and subsets of prostate tumors, where overexpression often correlates with more aggressive biology and worse outcomes. While not universally expressed at high levels, NTSR1 appears enriched in PSMA-low/negative advanced disease and NEPC, offering potential complementarity to PSMA-targeted therapies. Neurotensin/NTSR1 signaling has been implicated in promoting proliferation, invasion, and cross‑talk with growth factor receptors like EGFR, HER2, and HER3 in models of breast, pancreatic, and lung cancer.

Clinically, the initial phase 1 program deliberately avoids over‑narrowing the indication. The FDA‑cleared trial will enroll patients with advanced solid tumors that strongly express NTSR1 and have high unmet need—essentially, heavily pretreated patients who failed or relapsed after standard therapies.

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