Locnartecan

**Semantic type:** Pharmacologic Substance

**Definition:** A miniature drug conjugate composed of the irinotecan metabolite 7-ethyl-10-hydroxy-camptothecin (SN-38) conjugated, through a cleavable linker, to a ligand of chaperone protein heat shock protein 90 (Hsp90), with potential antineoplastic activity. Upon administration of locnartecan, the HSP90 ligand moiety targets HSP90, which allows the conjugate to penetrate, accumulate and be retained in the tumor cell. Once the linker is cleaved, the SN-38 moiety is released in a sustained manner. SN-38 then binds to and inhibits topoisomerase I by stabilizing the cleavable complex between topoisomerase I and DNA, which results in DNA breaks, inhibition of DNA replication and apoptosis. Compared to SN-38 alone, locnartecan preferentially targets, accumulates and is retained in the tumor cells due to its binding to Hsp90, which results in increased concentrations of SN-38 at the tumor site. This allows sustained release of SN-38 and leads to increased and prolonged efficacy while reducing toxicity to normal, healthy tissues. Hsp90, a chaperone protein upregulated and activated in a variety of tumor cells compared to normal healthy tissue, regulates the folding, stability and degradation of many oncogenic signaling proteins.

**Synonyms:** - HDC SN-38 - HSP90-targeted SN-38 Conjugate PEN-866 - LOCNARTECAN - PEN 866 - PEN-866 - PEN866 - STA-12-8666 - STA-8666